Compounds useful as modulators of TRPM8

ABSTRACT

The present invention includes compounds useful as modulators of TRPM8, such as compounds of Formulae (Ia), (Ib) and (Ic), and the subgenus and species thereof; personal products containing those compounds; and the use of those compounds and the personal products, particularly the use of increasing or inducing chemesthetic sensations, such as cooling or cold sensations.

FIELD OF THE INVENTION

The present invention relates to compounds useful as modulators ofTRPM8.

BACKGROUND OF THE INVENTION

The present invention provides compounds useful as modulators of theMelastatin Transient Receptor Potential Channel 8 (TRPM8). TRPM8 is achannel involved in the chemesthetic sensation, such as cool to coldtemperatures as well as the sensation of known cooling agents, such asMenthol and Icilin. However, many of the currently known TRPM8modulators have deficiencies with regard to strength and/or duration ofeffect, skin and/or mucosa irritation, odor, taste, solubility, and/ortoxicity.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a five- orsix-membered heterocyclic compound having structural Formula (Ia) or(Ib):

or a salt or solvate thereof;wherein

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted carbocyclyl, optionallysubstituted heteroaryl, and optionally substituted heterocyclyl;

R⁴ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

either R⁵ or R⁶ is optionally substituted C₁-C₃ alkyl; and the remainingR⁵ or R⁶ is selected from the group consisting of optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkoxy, optionally substituted alkylaryl,optionally substituted alkoxyaryl, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroalkyl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl; or alternatively, R⁵ and R⁶, taken togetherwith the atoms to which they are attached, form an optionallysubstituted carbocyclyl;

X and X¹ are independently CH or N; provided that X and X¹ are not bothCH;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, cyano, carboxy, optionally substitutedC₁-C₈ alkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted heteroalkyl, optionally substitutedalkylaryl, optionally substituted alkoxyaryl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl,-alkylene-carbonyl-aryl, -alkylene-carbonyl-heteroaryl,-alkylene-carbonyl-(substituted aryl), -alkylene-carbonyl-(substitutedheteroaryl), -alkylene-carbonyl-O-aryl,-alkylene-carbonyl-O-(substituted aryl), -alkylene-carbonyl-NR⁹-aryl,-alkylene-carbonyl-NR⁹-(substituted aryl),-alkylene-carbonyl-O-heteroaryl, -alkylene-carbonyl-O-(substitutedheteroaryl), -alkylene-carbonyl-NR⁹-heteroaryl,-alkylene-carbonyl-NR⁹-(substituted heteroaryl), OR⁹, and NR⁹R¹⁰; oralternatively, X and R⁸, or X¹ and R⁷, taken together, is independentlyO or S;

A is O, S, or NR⁵;

B and C are independently CH₂, C═O, or a covalent bond; provided that Band C are not both covalent bond; and

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substituted heteroalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted acylamido, and optionallysubstituted diacylamido; or alternatively, R⁹ and R¹⁰, together with theatoms to which they are bonded, form an optionally substitutedcycloheteroalkyl.

In one embodiment, the present invention provides a compound havingstructural Formula (Ic):

or a salt or solvate thereof;wherein

X is CR⁵ or N;

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are the same or different and are independently selected fromthe group consisting of hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl;

R⁴ is hydrogen, hydroxyl, alkoxy, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl; and

R⁵ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; or alternatively, R³ and R⁵, or R³ and R⁴,taken together with the atoms to which they are attached, form anoptionally substituted carbocyclyl or optionally substitutedheterocyclyl.

In another embodiment, the present invention provides a personal productcomprising a compound of the present invention, or a salt or solvatethereof.

In another embodiment, the present invention provides a method ofmodulating transient receptor potential channel melastatin member 8(TRPM8) comprising contacting the receptor with a compound of thepresent invention, or a salt or solvate thereof.

In another embodiment, the present invention provides a method ofmodulating the cooling sensation of a composition comprising combiningthe composition with a compound of the present invention, or a salt orsolvate thereof, to form a modified composition.

In another embodiment, the present invention provides a method ofinducing a cooling sensation in a human or animal comprising contactingthe human or animal with a compound of the present invention, or a saltor solvate thereof.

In another embodiment, the present invention provides a method oftreating a condition, disease, or disorder associated with a TRPM8receptor comprising administering to a subject in need of such treatmentan therapeutically effective amount of a compound of the presentinvention, or a salt or solvate thereof.

DETAILED DESCRIPTIONS OF THE INVENTION

Various embodiments and advantages of the present invention will be setforth in part in the description that follows, and in part will beobvious from the description, or may be learned by practice of theinvention. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention as described.

DEFINITIONS

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” or “and/or” is used as a function word to indicate that twowords or expressions are to be taken together or individually. The terms“comprising”, “having”, “including”, and “containing” are to beconstrued as open-ended terms (i.e., meaning “including, but not limitedto”). The endpoints of all ranges directed to the same component orproperty are inclusive and independently combinable.

The term “present compound(s)” or “compound(s) of the present invention”refers to compounds encompassed by structural formula disclosed herein,such as Formula (I), Formula (Ia), and includes any subgenus andspecific compounds within the formula whose structure is disclosedherein. Compounds may be identified either by their chemical structureand/or chemical name. When the chemical structure and chemical nameconflict, the chemical structure is determinative of the identity of thecompound. The compounds described herein may contain one or more chiralcenters and/or double bonds and therefore, may exist as stereoisomers,such as double-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds of the invention include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds may be hydrated, solvatedor N-oxides. Certain compounds may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated herein and are intended to be within the scope of thepresent invention. Further, it should be understood, when partialstructures of the compounds are illustrated, that brackets indicate thepoint of attachment of the partial structure to the rest of themolecule. The term “tautomer” as used herein refers to isomers thatchange into one another with great ease so that they can exist togetherin equilibrium.

“Alkyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic monovalent hydrocarbonradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. The term “alkyl” includes “cycloakyl” asdefined herein below. Typical alkyl groups include, but are not limitedto, methyl; ethyl; propyls such as propan-1-yl, propan-2-yl (isopropyl),cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.; and the like. In some embodiments, analkyl group comprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl) or 1 to 4 carbon atoms (C₁-C₄ alkyl). C₁-C₆alkyl is also known as “lower alkyl”.

It is noted that when an alkyl group is further connected to anotheratom, it becomes an “alkylene” group. In other words, the term“alkylene” refers to a divalent alkyl. For example, —CH₂CH₃ is an ethyl,while —CH₂CH₂— is an ethylene. That is, “Alkylene,” by itself or as partof another substituent, refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by theremoval of two hydrogen atoms from a single carbon atom or two differentcarbon atoms of a parent alkane, alkene or alkyne. The term “alkylene”includes “cycloalkylene” as defined herein below. The term “alkylene” isspecifically intended to include groups having any degree or level ofsaturation, i.e., groups having exclusively single carbon-carbon bonds,groups having one or more double carbon-carbon bonds, groups having oneor more triple carbon-carbon bonds and groups having mixtures of single,double and triple carbon-carbon bonds. In some embodiments, an alkylenegroup comprises from 1 to 20 carbon atoms (C₁-C₂₀ alkylene). In otherembodiments, an alkylene group comprises from 1 to 10 carbon atoms(C₁-C₁₀ alkylene). In still other embodiments, an alkylene groupcomprises from 1 to 6 carbon atoms (C₁-C₆ alkylene).

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic monovalent hydrocarbonradical having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The term “alkenyl” includes “cycloalkenyl” as defined hereinbelow. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. In someembodiments, an alkenyl group comprises from 2 to 20 carbon atoms(C₂-C₂₀ alkenyl). In other embodiments, an alkenyl group comprises from2 to 10 carbon atoms (C₂-C₁₀ alkenyl). In still other embodiments, analkenyl group comprises from 2 to 6 carbon atoms (C₂-C₆ alkenyl) or 2 to4 carbon atoms (C₂-C₄ alkenyl). C₂-C₆ alkenyl is also known as “loweralkenyl”.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic monovalent hydrocarbonradical having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In someembodiments, an alkynyl group comprises from 2 to 20 carbon atoms(C₂-C₂₀ alkynyl). In other embodiments, an alkynyl group comprises from2 to 10 carbon atoms (C₂-C₁₀ alkynyl). In still other embodiments, analkynyl group comprises from 2 to 6 carbon atoms (C₂-C₆ alkynyl) or 2 to4 carbon atoms (C₂-C₄ alkynyl). C₂-C₆ alkynyl is also known as “loweralkynyl”.

“Alkoxy,” by itself or as part of another substituent, refers to aradical of the formula —O—R¹⁹⁹, where R¹⁹⁹ is alkyl or substituted alkylas defined herein.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R²⁰⁰, where R²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 10 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. That is, arylakyl can also beconsidered as an alkyl substituted by aryl. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. In someembodiments, an arylalkyl group is (C₆-C₃₀) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₁₀)alkyl and the aryl moiety is (C₆-C₂₀) aryl. In other embodiments, anarylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) alkyl and the arylmoiety is (C₆-C₁₂) aryl. In still other embodiments, an arylalkyl groupis (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is (C₁-C₅) alkyl and the aryl moiety is (C₆-C₁₀)aryl.

“Carbocyclic,” or “Carbocyclyl,” by itself or as part of anothersubstituent, refers to a saturated or partially saturated, buy noyaromatic, cyclic monovalent hydrocarbon radical, including cycloalkyl,cycloalkenyl, and cycloalkynyl as defined herein. Typical carbocyclylgroups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Insome embodiments, the cycloalkyl group comprises from 3 to 10 ring atoms(C₃-C₁₀ cycloalkyl). In other embodiments, the cycloalkyl groupcomprises from 3 to 7 ring atoms (C₃-C₇ cycloalkyl). The carbocyclyl maybe further substituted by one or more heteroatoms including, but notlimited to, N, P, O, S, and Si, which attach to the carbon atoms of thecycloalkyl via monovalent or multivalent bond.

“Heteroalkyl,” by themselves or as part of other substituents, refer toalkyl groups, in which one or more of the carbon atoms, are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomicgroups which can replace the carbon atoms include, but are not limitedto, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—, —S(O)₂NH— andthe like and combinations thereof. The heteroatoms or heteroatomicgroups may be placed at any interior position of the alkyl group.Typical heteroatomic groups which can be included in these groupsinclude, but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—,—NR²⁰¹R²⁰²—, ═N—N═, —N═N—, —N═N—NR²⁰³R²⁰⁴, —PR²⁰⁵—, —P(O)₂—, —POR²⁰⁶—,—O—P(O)₂—, —SO—, —SO₂—, —SnR²⁰⁷R²⁰⁸— and the like, where R²⁰¹, R²⁰²,R²⁰³, R²⁰⁴, R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

“Heterocyclic,” or “Heterocyclyl,” by itself or as part of anothersubstituent, refers to a carbocyclic radical in which one or more carbonatoms are independently replaced with the same or different heteroatom.The heterocyclyl may be further substituted by one or more heteroatomsincluding, but not limited to, N, P, O, S, and Si, which attach to thecarbon atoms of the heterocyclyl via monovalent or multivalent bond.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Typical heterocyclyl groups include,but are not limited to, groups derived from epoxides, azirines,thiiranes, imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidone, quinuclidine, and the like. In someembodiments, the heterocyclyl group comprises from 3 to 10 ring atoms(3-10 membered heterocyclyl) In other embodiments, the heterocyclylgroup comprise from 5 to 7 ring atoms (5-7 membered heterocyclyl). Acycloheteroalkyl group may be substituted at a heteroatom, for example,a nitrogen atom, with a (C₁-C₆) alkyl group. As specific examples,N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl,N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinylare included within the definition of “heterocyclyl.” A heterocyclylgroup may be attached to the remainder of the molecule via a ring carbonatom or a ring heteroatom.

“Halo,” by itself or as part of another substituent refers to a radical—F, —Cl, —Br or —I.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“N-oxide”, also known as amine oxide or amine-N-oxide, means a compoundthat derives from a compound of the present invention via oxidation ofan amine group of the compound of the present invention. An N-oxidetypically contains the functional group R₃N⁺—O⁻ (sometimes written asR₃N═O or R₃N→O).

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Solvate” means a compound formed by solvation (the combination ofsolvent molecules with molecules or ions of the solute), or an aggregatethat consists of a solute ion or molecule, i.e., a compound of thepresent invention, with one or more solvent molecules. When water is thesolvent, the corresponding solvate is “hydrate”.

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), ═S⁻, —NR^(c)R^(c),═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s may be taken together with the nitrogenatom to which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl. As another specificexample, a substituted alkyl is meant to include -alkylene-O-alkyl,-alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(O)OR^(b),-alkylene-C(O)NR^(b)R^(b), and —CH₂—CH₂—C(O)—CH₃. The one or moresubstituent groups, taken together with the atoms to which they arebonded, may form a cyclic ring including cycloalkyl andcycloheteroalkyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl,—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S—, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined. Substituent groups from theabove lists useful for substituting other specified groups or atoms willbe apparent to those of skill in the art.

The term “substituted” specifically envisions and allows for one or moresubstitutions that are common in the art. However, it is generallyunderstood by those skilled in the art that the substituents should beselected so as to not adversely affect the useful characteristics of thecompound or adversely interfere with its function. Suitable substituentsmay include, for example, halogen groups, perfluoroalkyl groups,perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups,hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxygroups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups,arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxygroups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, carboxyl groups, alkoxycarbonyl groups,alkylaminocarbonyl groups, dialkylamino carbonyl groups, arylcarbonylgroups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonylgroups, cycloalkyl groups, cyano groups, C₁-C₆ alkylthio groups,arylthio groups, nitro groups, keto groups, acyl groups, boronate orboronyl groups, phosphate or phosphonyl groups, sulfamyl groups,sulfonyl groups, sulfinyl groups, and combinations thereof. In the caseof substituted combinations, such as “substituted arylalkyl,” either thearyl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents.Additionally, in some cases, suitable substituents may combine to formone or more rings as known to those of skill in the art.

The term “optionally substituted” denotes the presence or absence of thesubstituent group(s). That is, it means “substituted or unsubstituted”.For example, optionally substituted alkyl includes both unsubstitutedalkyl and substituted alkyl. The substituents used to substitute aspecified group can be further substituted, typically with one or moreof the same or different groups selected from the various groupsspecified above.

“Carrier” refers to a diluent, adjuvant, excipient or vehicle with whicha compound is administered.

The term “chemesthesis” or “chemesthetic sensation” herein refers to thesensibility of bodily surface, e.g., the skin and/or mucosal surfaceswhich arise either when the bodily surface is exposed to heat orcoldness or when chemical compounds activate receptors associated withsenses that mediate pain, touch, and thermal/cold perception.Particularly, these chemical-induced reactions do not fit into thetraditional sense categories of taste and smell. Examples ofchemesthetic sensations include the burn-like irritation from chilipepper, the coolness of menthol in mouthwashes and topical analgesiccreams, the stinging or tingling of carbonation in the nose and mouth,and the tear-induction of onions. That is, chemesthetic sensations canarise by direct chemical activation of ion channels on sensory nervefibers, e.g. TRPM8. Because chemoresponsive nerve fibers are present inall types of skin, chemesthetic sensations can be aroused from anywhereon the body's surface as well as from mucosal surfaces in the nose,mouth, eyes, etc.

A “chemesthetic sensation modifier” or “chemesthetic sensation modifyingagent” herein refers to a compound, or a salt or solvate thereof, whichmodulates, including enhancing or potentiating, inducing, or blocking,the chemesthetic sensation in an animal or a human.

A “chemesthetic sensation modulating amount” herein refers to an amountof a compound of the present invention that is sufficient to alter(either induce, increase, or decrease) the chemesthetic sensation in apersonal product, sufficiently to be perceived by an animal or humansubject. In many embodiments of the invention, at least about 0.001 ppmof the present compound would need to be present in order for mostanimal or human subjects to perceive a modulation of the chemestheticsensation in a personal product comprising the present compound. A broadrange of concentration that would typically be employed in order toeconomically provide a desirable degree of chemesthetic sensationmodulation can be from about 0.001 ppm to 1000 ppm, or from about 0.01ppm to about 500 ppm, or from about 0.05 ppm to about 300 ppm, or fromabout 0.1 ppm to about 200 ppm, or from about 0.5 ppm to about 150 ppm,or from about 1 ppm to about 100 ppm.

A “chemesthetic sensation inducing amount” or “chemesthetic sensationincreasing amount” herein refers to an amount of a compound that issufficient to induce or increase a chemesthetic sensation as perceivedby an animal or a human. A broad range of a chemesthetic sensationinducing/increasing amount can be from about 0.001 ppm to 100 ppm, or anarrow range from about 0.1 ppm to about 10 ppm. Alternative ranges ofchemesthetic sensation inducing/increasing amounts can be from about0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, fromabout 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.

As used herein, an “ingestible composition” includes any substance that,either alone or together with another substance, can be taken by mouthwhether intended for consumption or not. The ingestible compositionincludes both “food or beverage products” and “non-edible products”. By“Food or beverage products”, it is meant any edible product intended forconsumption by humans or animals, including solids, semi-solids, orliquids (e.g., beverages). The term “non-edible products” or“noncomestible composition” includes any product or composition that canbe taken by humans or animals for purposes other than consumption or asfood or beverage. For example, the non-edible product or noncomestiblecomposition includes supplements, nutraceuticals, functional foodproducts (e.g., any fresh or processed food claimed to have ahealth-promoting and/or disease-preventing properties beyond the basicnutritional function of supplying nutrients), pharmaceutical and overthe counter medications, oral care products such as dentifrices andmouthwashes, cosmetic products such as sweetened lip balms and otherpersonal care products that may or may not contain any sweetener.

A “ingestibly acceptable carrier or excipient” is a medium and/orcomposition that is used to prepare a desired dispersed dosage form ofthe inventive compound, in order to administer the inventive compound ina dispersed/diluted form, so that the biological effectiveness of theinventive compound is maximized. The medium and/or composition may be inany form depending on the intended use of a product, e.g., solid,semi-solid, liquid, paste, gel, lotion, cream, foamy material,suspension, solution, or any combinations thereof (such as a liquidcontaining solid contents). Ingestibly acceptable carriers includes manycommon food ingredients, such as water at neutral, acidic, or basic pH,fruit or vegetable juices, vinegar, marinades, beer, wine, naturalwater/fat emulsions such as milk or condensed milk, edible oils andshortenings, fatty acids and their alkyl esters, low molecular weightoligomers of propylene glycol, glyceryl esters of fatty acids, anddispersions or emulsions of such hydrophobic substances in aqueousmedia, salts such as sodium chloride, wheat flours, solvents such asethanol, solid edible diluents such as vegetable powders or flours, orother liquid vehicles; dispersion or suspension aids; surface activeagents; isotonic agents; thickening or emulsifying agents,preservatives; solid binders; lubricants and the like.

A “flavor” herein refers to the perception of taste in a subject, whichinclude sweet, sour, salty, bitter and umami (also known as savory). Thesubject may be a human or an animal.

A “flavoring agent” herein refers to a compound or the ingestiblyacceptable salt or solvate thereof that induces a flavor or taste in ananimal or a human. The flavoring agent can be natural, semi-synthetic,or synthetic.

A “modulator” herein refers to a compound that can regulate the activityof TRPM8. Such regulation includes activating TRPM8, blocking TRPM8, orpotentiating/reducing the activation of TRPM8. That is, the modulatorsinclude agonists, antagonists, enhancers, and etc.

A “personal product”, as used herein, refers to any product that is usedby or useful for a person or animal, optionally in contact with theperson or animal during its intended use, e.g., in surface contact suchas skin or mucosa contact with the person or animal during its intendeduse.

“Treating” or “treatment” of any condition, disease or disorder refersto ameliorating the condition, disease or disorder (i.e., arresting orreducing the development of the condition, disease or disorder or atleast one of the clinical symptoms thereof). In other embodiments“treating” or “treatment” refers to ameliorating at least one physicalparameter, which may not be discernible by the patient. In yet otherembodiments, “treating” or “treatment” refers to inhibiting thecondition, disease or disorder, either physically, (e.g., stabilizationof a discernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In yet other embodiments, “treating” or“treatment” refers to delaying the onset of the condition, disease ordisorder.

“Therapeutically effective amount” means the amount of the presentcompound that, when administered to a patient for treating a condition,disease or disorder, is sufficient to effect such treatment for thecondition, disease or disorder. The “therapeutically effective amount”will vary depending on the compound, the condition, disease or disorderand its severity and the age, weight, etc., of the patient to betreated.

Embodiments of the Compounds

In one embodiment, the present invention provides a five- orsix-membered heterocyclic compound having structural Formula (Ia) or(Ib):

or a salt or solvate thereof;wherein

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted carbocyclyl, optionallysubstituted heteroaryl, and optionally substituted heterocyclyl;

R⁴ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

either R⁵ or R⁶ is optionally substituted C₁-C₃ alkyl; and the remainingR⁵ or R⁶ is selected from the group consisting of optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkoxy, optionally substituted alkylaryl,optionally substituted alkoxyaryl, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroalkyl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl; or alternatively, R⁵ and R⁶, taken togetherwith the atoms to which they are attached, form an optionallysubstituted carbocyclyl;

X and X¹ are independently CH or N; provided that X and X¹ are not bothCH;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, cyano, carboxy, optionally substitutedC₁-C₈ alkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted heteroalkyl, optionally substitutedalkylaryl, optionally substituted alkoxyaryl, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl,-alkylene-carbonyl-aryl, -alkylene-carbonyl-heteroaryl,-alkylene-carbonyl-(substituted aryl), -alkylene-carbonyl-(substitutedheteroaryl), -alkylene-carbonyl-O-aryl,-alkylene-carbonyl-O-(substituted aryl), -alkylene-carbonyl-NR⁹-aryl,-alkylene-carbonyl-NR⁹-(substituted aryl),-alkylene-carbonyl-O-heteroaryl, -alkylene-carbonyl-O-(substitutedheteroaryl), -alkylene-carbonyl-NR⁹-heteroaryl,-alkylene-carbonyl-NR⁹-(substituted heteroaryl), OR⁹, and NR⁹R¹⁰; oralternatively, X and R⁸, or X¹ and R⁷, taken together, is independentlyO or S;

A is O, S, or NR⁵;

B and C are independently CH₂, C═O, or a covalent bond; provided that Band C are not both covalent bond; and

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substituted heteroalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted acylamido, and optionallysubstituted diacylamido; or alternatively, R⁹ and R¹⁰, together with theatoms to which they are bonded, form an optionally substitutedcycloheteroalkyl.

In one embodiment of Formula (Ia) or (Ib), the optionally substitutedcarbocyclyl or optionally substituted heterocyclyl is optionallysubstituted cycloalkyl, optionally substituted cycloalkenyl, optionallysubstituted cycloheteroalkyl, or optionally substitutedcycloheteroalkenyl.

In one embodiment, the present invention provides a five-memberedheterocyclic compound having structural Formula (Ia) or (Ib):

or a salt or solvate thereof;wherein

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted carbocyclyl, optionallysubstituted heteroaryl, and optionally substituted heterocyclyl;

R⁴ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

either R⁵ or R⁶ is C₁-C₃ alkyl, and the remaining R⁵ or R⁶ is selectedfrom the group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted alkylaryl, optionally substituted heteroalkyl, optionallysubstituted carbocyclyl, or optionally substituted heterocyclyl; oralternatively, R⁵ and R⁶, taken together with the atoms to which theyare attached, form an optionally substituted carbocyclic ring;

X and X¹ are N;

R⁷ is hydrogen, or optionally substituted C₁-C₆ alkyl;

R⁸ is selected from the group consisting of optionally substituted C₁-C₈alkyl, optionally substituted alkenyl, -alkylene-carbonyl-aryl,-alkylene-carbonyl-heteroaryl, -alkylene-carbonyl-(substituted aryl),-alkylene-carbonyl-(substituted heteroaryl), -alkylene-carbonyl-O-aryl,-alkylene-carbonyl-O-(substituted aryl), -alkylene-carbonyl-NR⁹-aryl,-alkylene-carbonyl-NR⁹-(substituted aryl),-alkylene-carbonyl-O-heteroaryl, -alkylene-carbonyl-O-(substitutedheteroaryl), -alkylene-carbonyl-NR⁹-heteroaryl, and-alkylene-carbonyl-NR⁹-(substituted heteroaryl);

R⁹ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted acylamido, and optionally substituted diacylamido;

A is O;

B is CH₂, or C═O; and

C is a covalent bond.

In one embodiment of Formula (Ia), R¹ is optionally substituted aryl oroptionally substituted heteroaryl. In one embodiment of R¹, theoptionally substituted heteroaryl is a five- or six-membered heteroarylcontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur. In one embodiment of R¹, the optionally substituted aryl isoptionally substituted phenyl; and the optionally substituted heteroarylis selected from the group consisting of pyrrolyl, thienyl, pyridyl,pyrimidyl, furanyl, and pyrazolyl, each of which is optionallysubstituted.

In one embodiment of Formula (Ia), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,and optionally substituted heterocyclyl. In one embodiment of R², theoptionally substituted carbocyclyl is an optionally substituted 5- or6-membered monocyclic carbocyclyl, or an optionally substituted 9- to12-membered bicyclic carbocyclyl.

In one embodiment of Formula (Ia), R³ is optionally substituted alkyl oroptionally substituted alkenyl. In one embodiment of Formula (Ia), R³ isoptionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Ia), R² is optionally substitutedcarbocyclyl; and R³ is optionally substituted alkyl.

In one embodiment of Formula (Ia), R⁴ is optionally substituted alkyl.In one embodiment of Formula (Ia), R⁴ is optionally substituted C₁-C₄alkyl.

In one embodiment of Formula (Ia), the optional substituent may be oneor more substituent(s) selected from the group consisting of alkyl,alkoxy, hydroxyl, amino, N-alkyl amino, N-dialkyl amino, halo, nitro,cyano, acyl, carboxyl, carboxyl ester, or amide; or two substituents,together with the atoms to which they are attached, form an optionallysubstituted carbocyclyl or heterocyclyl containing one or moreheteroatom(s) selected from nitrogen, oxygen, and sulfur.

In some specific embodiments of Formula (Ia), the present compound isselected from the group consisting of:

wherein a carbon atom marked with an asterisk indicates a chiral centerwhich may be in a configuration of R, or S, or mixed R and S includingracemic R and S. In one embodiment, the carbon atom marked with anasterisk indicates a chiral center, and the compound is a racemicmixture. In other embodiments, the carbon atom marked with an asteriskindicates a chiral center, and the chiral center has an S configuration.In certain embodiments, the carbon atom marked with an asteriskindicates a chiral center, and the compound is a mixture enriched in oneisomer relative to the other isomer (e.g., enriched in the R isomerrelative to the S isomer; or, enriched in the S isomer relative to the Risomer). In some embodiments, the present compounds may bediastereomeric. In some embodiments, the compound may be a diastereomerand may be optically pure. In other embodiments, the compound may not beoptically pure, but may be enriched in one diastereomer. In still otherembodiments, the compound may be a mixture of all possiblediastereomers.

In one embodiment of Formula (Ib), either R⁵ or R⁶, is selected fromC₁-C₃ alkyl, and the remaining R⁵ or R⁶ is selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedalkylaryl, optionally substituted heteroalkyl, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl; or alternatively,R⁵ and R⁶, taken together with the atoms to which they are attached,form an optionally substituted carbocyclyl;

X and X¹ are N;

R⁷ is hydrogen, or optionally substituted C₁-C₄ alkyl;

R⁸ is represented by (a), (b), or (c):

Ar and Ar¹ are independently optionally substituted aryl, or optionallysubstituted heteroaryl;

R¹¹ is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₄ alkyl, optionally substituted aryl, optionallysubstituted heteroalkyl, or optionally substituted heteroaryl;

R¹² and R¹³ are independently C₁-C₄ alkyl; or alternatively, R¹² andR¹³, together with the atoms to which they are bonded, form a 5-, 6- or7-membered optionally substituted cycloheteroalkyl ring;

A is selected from O;

B is selected from CH₂ or C═O;

C represents a chemical bond.

In one embodiment of Formula (Ib), either R⁵ or R⁶ is selected fromC₁-C₃ alkyl, and the remaining R⁵ or R⁶ is selected from the groupconsisting of optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, optionally substituted C₃-C₆ alkyl,optionally substituted C₃-C₆ alkenyl, and optionally substituted C₁-C₃alkyl-aryl; or alternatively, R⁵ and R⁶, taken together with the atomsto which they are attached, form an optionally substituted C₃-C₅cycloalkyl or optionally substituted C₃-C₅ cycloalkenyl ring.

X and X¹ are N;

R⁷ is hydrogen, or C₁-C₄ alkyl;

R⁸ is represented by (a), (b) or (c):

Ar and Ar¹ are independently optionally substituted phenyl or optionallysubstituted heteroaryl; and

R¹¹ is hydrogen, optionally substituted C₁-C₄ alkyl, optionallysubstituted aryl, optionally substituted heteroalkyl, or optionallysubstituted heteroaryl;

R¹² and R¹³ are independently C₁-C₄ alkyl, or alternatively, R¹² andR¹³, together with the atoms to which they are bonded, form a 5-, 6- or7-membered cycloheteroalkyl ring;

A is O;

B is CH₂, or CO; and

C is a covalent bond.

In one embodiment of Formula (Ib), either R⁵ or R⁶ is C₁-C₃ alkyl, andthe remaining R⁵ or R⁶ is selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkylaryl, optionallysubstituted heteroalkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, optionally substituted cycloheteroalkyl, andoptionally substituted cycloheteroalkenyl;

X and X¹ are N;

R⁷ is C₁-C₄ alkyl;

R⁸ is represented by (a), (b) or (c):

Ar and Ar¹ are independently optionally substituted aryl or optionallysubstituted heteroaryl;

R¹² is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₄ alkyl, optionally substituted aryl, optionallysubstituted heteroalkyl, or optionally substituted heteroaryl;

R¹² and R¹³ are independently C₁-C₄ alkyl, or alternatively, R¹² andR¹³, together with the atoms to which they are bonded, form a 5-, 6- or7-membered optionally substituted cycloheteroalkyl ring;

A is O;

B is CH₂, or C═O; and

C is CH₂, or C═O.

In one embodiment of Formula (Ib), either R⁵ or R⁶ is selected fromC₁-C₃ alkyl, and the remaining R⁵ or R⁶ is selected from the groupconsisting of optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, optionally substituted C₃-C₆ alkyl,optionally substituted C₃-C₆ alkenyl, and optionally substituted C₁-C₃alkyl-aryl;

X and X¹ are N;

R⁷ is C₁-C₃ alkyl;

R⁸ is represented by (a), (b) or (c):

Ar and Ar¹ are independently optionally substituted phenyl, oroptionally substituted heteroaryl;

R¹¹ is selected from the group consisting of hydrogen or optionallysubstituted C₁-C₄ alkyl;

R¹² and R¹³ are independently C₁-C₄ alkyl; or alternatively, R¹² andR¹³, together with the atoms to which they are bonded, form a 5-, 6- or7-membered cycloheteroalkyl ring;

A is O;

B is CH₂, or C═O; and

C is CH₂, or C═O.

In one embodiment of Formula (Ib), the optional substituent may be oneor more substituent(s) selected from the group consisting of alkyl,alkoxy, hydroxyl, amino, N-alkyl amino, N-dialkyl amino, halo, nitro,cyano, acyl, carboxyl, carboxyl ester, or amide; or two substituents,together with the atoms to which they are attached, form an optionallysubstituted carbocyclyl or heterocyclyl containing one or moreheteroatom(s) selected from nitrogen, oxygen, and sulfur.

In some specific embodiments of Formula (Ib), the present compounds areselected from the compounds listed in Table X below:

TABLE X Example Structure 2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

2.10

2.11

2.12

2.13

2.14

2.15

2.16

2.17

2.18

2.19

2.20

2.21

2.22

2.23

2.24

2.25

2.26

2.27

2.28

2.29

2.31

2.31

2.32

2.33

2.34

2.35

2.36

2.37

2.38

2.39

2.40

2.41

2.42

2.43

2.44

2.45

2.46

2.47

2.48

2.49

2.50

2.51

2.52

2.53

2.54

2.55

2.56

2.57

2.58

2.59

2.60

2.61

2.62

2.63

2.64

2.65

2.66

2.67

2.68

2.69

2.70

2.71

2.72

2.73

2.74

2.75

2.76

2.77

2.78

2.79

2.80

2.81

2.82

2.83

2.84

2.85

2.86

2.87

2.88

2.89

2.90

2.91

2.92

2.93

2.94

2.95

2.96

2.97

2.98

2.99

2.100

2.101

2.102

2.103

2.104

2.105

2.106

2.107

2.108

2.109

2.110

2.111

2.112

2.113

2.114

2.115

2.116

2.117

2.118

2.119

2.120

2.121

2.122

2.123

2.124

2.125

2.126

2.127

2.128

2.129

2.130

2.131

2.132

2.133

2.134

2.135

2.136

2.137

2.138

2.139

2.140

2.141

2.142

2.143

2.144

2.145

2.146

2.147

2.148

2.149

In one embodiment, the present invention provides a compound havingstructural Formula (Ic):

or a salt or solvate thereof;wherein

X is CR⁵ or N;

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are the same or different and are independently selected fromthe group consisting of hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl;

R⁴ is hydrogen, hydroxyl, alkoxy, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl; and

R⁵ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; or alternatively, R³ and R⁵, or R³ and R⁴,taken together with the atoms to which they are attached, form anoptionally substituted carbocyclyl or optionally substitutedheterocyclyl.

In one embodiment of Formula (Ic), X is CH or N;

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R² and R³ are the same or different and are independently selected fromthe group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; and

R⁴ is hydrogen, hydroxyl, alkoxy, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl.

In one embodiment of Formula (Ic), R¹ is optionally substituted aryl oroptionally substituted heteroaryl. In one embodiment of R¹, theoptionally substituted aryl is optionally substituted phenyl. In oneembodiment of R¹, the optionally substituted heteroaryl is a five- orsix-membered heteroaryl containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur. In one embodiment of R¹, the optionallysubstituted heteroaryl is selected from the group consisting ofpyrrolyl, thienyl, pyridyl, imidazolyl, triazolyl, thiazolyl, pyrimidyl,furanyl, and pyrazolyl, each of which is optionally substituted.

In one embodiment of Formula (Ic), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,or optionally substituted heterocyclyl. In one embodiment of R², theoptionally substituted carbocyclyl is an optionally substituted 5- or6-membered monocyclic carbocyclyl.

In one embodiment of Formula (Ic), R³ is hydrogen, optionallysubstituted alkyl, or optionally substituted alkenyl. In one embodimentof Formula (Ic), R³ is optionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Ic), R² is optionally substitutedcarbocyclyl; and R³ is optionally substituted alkyl.

In one embodiment of Formula (Ic), R⁴ is hydrogen, hydroxyl, alkoxy, oroptionally substituted alkyl. In one embodiment of Formula (Ic), R⁴ isoptionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Ic), X is N or CH.

In one embodiment of Formula (Ic), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,or optionally substituted heterocyclyl; and R³ is optionally substitutedalkyl or optionally substituted alkenyl.

In one embodiment of Formula (Ic), X is CH;

R¹ is optionally substituted aryl or optionally substituted heteroaryl;

R² is optionally substituted carbocyclyl;

R³ is optionally substituted alkyl; and

R⁴ is hydrogen or optionally substituted alkyl.

In one embodiment of Formula (Ic), the optional substituent may be oneor more substituent(s) selected from the group consisting of alkyl,alkoxy, hydroxyl, amino, N-alkyl amino, N-dialkyl amino, halo, nitro,cyano, acyl, carboxyl, carboxyl ester, or amide; or two substituents,together with the atoms to which they are attached, form an optionallysubstituted carbocyclyl or heterocyclyl containing one or moreheteroatom(s) selected from nitrogen, oxygen, and sulfur.

In one embodiment of Formula (Ic), the compound has structural Formula(Id):

or a salt or solvate thereof;wherein

R¹ is optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl;

R², R³ and R⁵ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl, provided that R² is not hydrogen, and R³ and R⁵ are notboth hydrogen; or alternatively, R² and R³, taken together with thecarbon atom to which they are attached, forms a moiety with a doublebond: ═C(R⁶R⁷); or alternatively, R³ and R⁵, or R⁴ and R⁵, takentogether with the atoms to which they are attached, form an optionallysubstituted carbocyclyl or optionally substituted heterocyclyl; and

R⁴ is hydrogen, hydroxyl, alkoxy, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl;

R⁶ and R⁷ are independently hydrogen, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl; or alternatively, R⁶ and R⁷, taken together with thecarbon atom to which they are attached, form an an optionallysubstituted carbocyclyl or optionally substituted heterocyclyl.

In one embodiment of Formula (Id), R¹ is optionally substituted aryl oroptionally substituted heteroaryl. In one embodiment of R², theoptionally substituted aryl is optionally substituted phenyl; and theoptionally substituted heteroaryl is a five- or six-membered heteroarylcontaining one or more heteroatoms selected from nitrogen, oxygen, andsulfur. In one embodiment of R², the substituted heteroaryl is selectedfrom the group consisting of pyrrolyl, thienyl, pyridyl, imidazolyl,triazolyl, thiazolyl, pyrimidyl, furanyl, and pyrazolyl, each of whichis optionally substituted.

In one embodiment of Formula (Id), R² is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl; and R³ and R⁵ are independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,and optionally substituted heterocyclyl, provided that R³ and R⁵ are notboth hydrogen.

In one embodiment of Formula (Id), R³ is optionally substituted alkyl,or optionally substituted alkenyl; and R⁵ is optionally substitutedalkyl, or optionally substituted alkenyl. In one embodiment of Formula(Id), R³ is optionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Id), R⁵ is optionally substituted C₁-C₄alkyl.

In one embodiment of Formula (Id), R³ and R⁵, taken together with thecarbon atom to which they are attached, form an optionally substitutedcarbocyclyl. In one embodiment, the optionally substituted carbocyclylis an optionally substituted 3-, 4-, or 5-membered monocycliccarbocyclyl.

In one embodiment of Formula (Id), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,or optionally substituted heterocyclyl. In one embodiment of R², theoptionally substituted carbocyclyl is an optionally substituted 5- or6-membered monocyclic carbocyclyl.

In one embodiment of Formula (Id), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,or optionally substituted heterocyclyl;

R³ is optionally substituted alkyl or optionally substituted alkenyl;and

R⁵ is optionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Id), R² is optionally substitutedcarbocyclyl;

R³ is optionally substituted alkyl; and

R⁵ is optionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Id), R⁴ is hydrogen, hydroxyl, alkoxy, oroptionally substituted alkyl. In one embodiment of Formula (Id), R⁴ ishydrogen or optionally substituted C₁-C₄ alkyl.

In one embodiment of Formula (Id), R¹ is optionally substituted aryl oroptionally substituted heteroaryl;

R² is optionally substituted carbocyclyl;

R³ is optionally substituted alkyl;

R⁵ is optionally substituted C₁-C₄ alkyl; and

R⁴ is hydrogen or optionally substituted alkyl.

In one embodiment of Formula (Id), R² and R³, taken together with thecarbon atom to which they are attached, forms a moiety with a doublebond: ═C(R⁶R⁷); wherein R⁶ and R⁷, taken together with the carbon atomto which they are attached, form an optionally substituted carbocyclyl.

In one embodiment of Formula (Id), R² is optionally substituted aryl,optionally substituted carbocyclyl, optionally substituted heteroaryl,or optionally substituted heterocyclyl; R³ is hydrogen, optionallysubstituted alkyl, or optionally substituted alkenyl; and R⁴ and R⁵,taken together with the atoms to which they are attached, form anoptionally substituted heterocyclyl.

In some specific embodiments of the present invention, the presentcompounds are selected from the compounds listed in Table Y below. The“Ex#” below denotes Example number.

Ex# Structure 3.1

3.2

3.3

3.4

3.5

3.6

3.7

3.8

3.9

3.10

3.11

3.12

3.13

3.14

3.15

3.16

3.17

3.18

3.19

3.20

3.21

3.22

3.23

3.24

3.25

3.26

3.27

3.28

3.29

3.30

3.31

3.32

3.33

3.34

3.35

3.36

3.37

3.38

3.39

3.40

3.41

3.42

3.43

3.44

3.45

3.46

3.47

3.48

3.49

3.50

3.51

3.52

3.53

3.54

3.55

3.56

3.57

3.58

3.59

3.60

3.61

Embodiments of the Utilities of the Present Compounds

The compounds of the present invention, or a salt or solvate thereof,can be used as modulators, e.g., agonists, of the TRPM8 receptor inpersonal products for modulating, e.g., inducing, chemestheticsensations, particularly the cold or cool sensations.

The present compounds are important to the flavorings and fragranceindustry because they can increase or induce/generate a cooling or coldsensation which is often associated with freshness and cleanliness.

As modulators of the TRPM8 receptor, the present compounds also haverepellent effect on insects, therapeutic effect in antitumor treatments(e.g. an influencing of prostate tumors), activity in the treatment ofinflammatory pain/hyperalgesia, and efficacy (as TRPM8 antagonists) inthe treatment of bladder syndrome or overactive bladder.

The personal product can be provided as a composition, which comprisesone or more of the present compound and optionally at least one carrier.The composition can be in any physical form, such as a solid,semi-solid, plaster, solution, suspension, lotion, cream, foam, gel,paste, emulsion, or a combination thereof. Examples of the compositioninclude, but are not limited to, a pharmaceutical composition, aningestible composition, a chemesthetic concentrate, a personal carecomposition, and a combination thereof. In one embodiment of the presentinvention, the composition comprises a chemesthetic sensation modulatingamount of the present compound. In another embodiment of the presentinvention, the composition comprises a chemesthetic sensation inducingamount of the present compound. In certain embodiments, the chemestheticsensation is a cold or cooling sensation. In one embodiment of thecomposition, the present compound is in a concentration ranging fromabout 0.0001 ppm to 100,000 ppm. In another embodiment of thecomposition, the present compound is in a concentration ranging fromabout 0.001 ppm to 10,000 ppm. In another embodiment of the composition,the present compound is in a concentration ranging from about 0.01 ppmto 1,000 ppm. In another embodiment of the composition, the presentcompound is in a concentration ranging from about 0.1 ppm to 500 ppm. Inanother embodiment of the composition, the present compound is in aconcentration ranging from about 1 ppm to 500 ppm. In another embodimentof the composition, the present compound is in a concentration rangingfrom about 10 ppm to 500 ppm. In another embodiment of the composition,the present compound is in a concentration ranging from about 1 ppm to400 ppm.

The present ingestible composition typically comprises one or morecompounds of the present invention and at least one ingestiblyacceptable carrier. The ingestible composition includes both “food orbeverage products” and “non-edible products”. By “food or beverageproducts”, it is meant any edible product intended for consumption byhumans or animals, including solids, semi-solids, or liquids (e.g.,beverages). The term “non-edible products” or “noncomestiblecomposition” includes nutraceutical compositions, dietary supplements,nutritional compositions, and functional food products (e.g., any freshor processed food claimed to have a health-promoting and/ordisease-preventing properties beyond the basic nutritional function ofsupplying nutrients).

In one embodiment, the present compounds are added to food or beverageproducts or formulations. Examples of food and beverage products orformulations include, but are not limited to coatings, frostings, orglazes for comestible products or any entity included in the Soupcategory, the Dried Processed Food category, the Beverage category, theReady Meal category, the Canned or Preserved Food category, the FrozenProcessed Food category, the Chilled Processed Food category, the SnackFood category, the Baked Goods category, the Confectionary category, theDairy Product category, the Ice Cream category, the Meal Replacementcategory, the Pasta and Noodle category, and the Sauces, Dressings,Condiments category, the Baby Food category, and/or the Spreadscategory.

In general, the Soup category refers to canned/preserved, dehydrated orfreeze dried, instant, chilled, UHT and frozen soup. For the purpose ofthis definition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consommé) to sauces (cream or cheese-based soups). The dehydrated orfreeze dried soups include dehydrated soup mixes, dehydrated instantsoups, and dehydrated ready-to-cook soups.

The Beverage category usually means beverages, beverage mixes andconcentrates, including but not limited to, carbonated andnon-carbonated beverages, alcoholic and non-alcoholic beverages, readyto drink beverages, liquid concentrate formulations for preparingbeverages such as sodas, and dry powdered beverage precursor mixes. TheBeverage category also includes alcoholic drinks, the soft drinks,sports drinks, isotonic beverages, and hot drinks. The alcoholic drinksinclude, but are not limited to beer, cider/perry, FABs, wine, andspirits. The soft drinks include, but are not limited to carbonates,such as colas and non-cola carbonates; fruit juice, such as juice,nectars, juice drinks and fruit flavored drinks; bottled water, whichincludes sparkling water, spring water and purified/table water;functional drinks, which can be carbonated or still and include sport,energy or elixir drinks; concentrates, such as liquid and powderconcentrates in ready to drink measure. The drinks, either hot or cold,include, but are not limited to coffee or ice coffee, such as fresh,instant, and combined coffee; tea or ice tea, such as black, green,white, oolong, and flavored tea; and other drinks including flavor-,malt- or plant-based powders, granules, blocks or tablets mixed withmilk or water.

The Snack Food category generally refers to any food that can be a lightinformal meal including, but not limited to Sweet and savory snacks andsnack bars. Examples of snack food include, but are not limited to fruitsnacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn,pretzels, nuts and other sweet and savory snacks. Examples of snack barsinclude, but are not limited to granola/muesli bars, breakfast bars,energy bars, fruit bars and other snack bars.

The Baked Goods category generally refers to any edible product theprocess of preparing which involves exposure to heat or excessivesunlight. Examples of baked goods include, but are not limited to bread,buns, cookies, muffins, cereal, toaster pastries, pastries, waffles,tortillas, biscuits, pies, bagels, tarts, quiches, cake, any bakedfoods, and any combination thereof.

The Ice Cream category generally refers to frozen dessert containingcream and sugar and flavoring. Examples of ice cream include, but arenot limited to: impulse ice cream; take-home ice cream; frozen yoghurtand artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean),and rice-based ice creams.

The Confectionary category generally refers to edible product that issweet to the taste. Examples of confectionary include, but are notlimited to candies, gelatins, chocolate confectionery, sugarconfectionery, gum, and the likes and any combination products.

The Meal Replacement category generally refers to any food intended toreplace the normal meals, particularly for people having health orfitness concerns. Examples of meal replacement include, but are notlimited to slimming products and convalescence products.

The Ready Meal category generally refers to any food that can be servedas meal without extensive preparation or processing. The ready mealincludes products that have had recipe “skills” added to them by themanufacturer, resulting in a high degree of readiness, completion andconvenience. Examples of ready meal include, but are not limited tocanned/preserved, frozen, dried, chilled ready meals; dinner mixes;frozen pizza; chilled pizza; and prepared salads.

The Pasta and Noodle category includes any pastas and/or noodlesincluding, but not limited to canned, dried and chilled/fresh pasta; andplain, instant, chilled, frozen and snack noodles.

The Canned/Preserved Food category includes, but is not limited tocanned/preserved meat and meat products, fish/seafood, vegetables,tomatoes, beans, fruit, ready meals, soup, pasta, and othercanned/preserved foods.

The Frozen Processed Food category includes, but is not limited tofrozen processed red meat, processed poultry, processed fish/seafood,processed vegetables, meat substitutes, processed potatoes, bakeryproducts, desserts, ready meals, pizza, soup, noodles, and other frozenfood.

The Dried Processed Food category includes, but is not limited to rice,breading, dessert mixes, dried ready meals, dehydrated soup, instantsoup, dried pasta, plain noodles, dehydrated or ambient preparations ofready-made dishes, meals, and single serve entrees including potato andrice dishes, and instant noodles.

The Chilled Processed Food category includes, but is not limited tochilled processed meats, processed fish/seafood products, lunch kits,fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pastaand noodles.

The Sauces, Dressings and Condiments category includes, but is notlimited to tomato pastes and purees, marinades, bouillon and bouillonlike products in pressed tubes, tablets, or powder or granulated form,stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces,soy based sauces, pasta sauces, barbecue sauces, wet/cooking sauces, drysauces/powder mixes, ketchup, mayonnaise, mustard, salad dressings,salad toppings, vinaigrettes, dips, pickled products, liquid recipemixes, concentrates, and other sauces, dressings and condiments.

The Baby Food category includes, but is not limited to milk- orsoybean-based formula; and prepared, dried and other baby food.

The Spreads category includes, but is not limited to jams and preserves,honey, batter mixes, shelf stable spreads, chocolate spreads, nut basedspreads, and yeast based spreads.

The Dairy Product category generally refers to edible product producedfrom mammal's milk. Examples of dairy product include, but are notlimited to drinking milk products, cheese, yoghurt and sour milk drinks,and other dairy products.

Additional examples for comestible composition, particularly food andbeverage products or formulations, are provided as follows. Exemplarycomestible compositions include one or more confectioneries, chocolateconfectionery, tablets, countlines, bagged selflines/softlines, boxedassortments, standard boxed assortments, twist wrapped miniatures,seasonal chocolate, chocolate with toys, alfajores, other chocolateconfectionery, mints, standard mints, power mints, boiled sweets,pastilles, gums, jellies and chews, toffees, caramels and nougat,medicated confectionery, lollipops, liquorices, other sugarconfectionery, gum, chewing gum, sugarized gum, sugar-free gum,functional gum, bubble gum, bread, packaged/industrial bread,unpackaged/artisanal bread, pastries, cakes, packaged/industrial cakes,unpackaged/artisanal cakes, cookies, chocolate coated biscuits, sandwichbiscuits, filled biscuits, savory biscuits and crackers, breadsubstitutes, breakfast cereals, rte cereals, family breakfast cereals,flakes, muesli, other cereals, children's breakfast cereals, hotcereals, ice cream, impulse ice cream, single portion dairy ice cream,single portion water ice cream, multi-pack dairy ice cream, multi-packwater ice cream, take-home ice cream, take-home dairy ice cream, icecream desserts, bulk ice cream, take-home water ice cream, frozenyoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurizedmilk, full fat fresh/pasteurized milk, semi skimmed fresh/pasteurizedmilk, long-life/uht milk, full fat long life/uht milk, semi skimmed longlife/uht milk, fat-free long life/uht milk, goat milk,condensed/evaporated milk, plain condensed/evaporated milk, flavored,functional and other condensed milk, flavored milk drinks, dairy onlyflavored milk drinks, flavored milk drinks with fruit juice, soy milk,sour milk drinks, fermented dairy drinks, coffee whiteners, powder milk,flavored powder milk drinks, cream, cheese, processed cheese, spreadableprocessed cheese, unspreadable processed cheese, unprocessed cheese,spreadable unprocessed cheese, hard cheese, packaged hard cheese,unpackaged hard cheese, yoghurt, plain/natural yoghurt, flavoredyoghurt, fruited yoghurt, probiotic yoghurt, drinking yoghurt, regulardrinking yoghurt, probiotic drinking yoghurt, chilled and shelf-stabledesserts, dairy-based desserts, soy-based desserts, chilled snacks,fromage frais and quark, plain fromage frais and quark, flavored fromagefrais and quark, savory fromage frais and quark, sweet and savorysnacks, fruit snacks, chips/crisps, extruded snacks, tortilla/cornchips, popcorn, pretzels, nuts, other sweet and savory snacks, snackbars, granola bars, breakfast bars, energy bars, fruit bars, other snackbars, meal replacement products, slimming products, convalescencedrinks, ready meals, canned ready meals, frozen ready meals, dried readymeals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza,soup, canned soup, dehydrated soup, instant soup, chilled soup, hotsoup, frozen soup, pasta, canned pasta, dried pasta, chilled/freshpasta, noodles, plain noodles, instant noodles, cups/bowl instantnoodles, pouch instant noodles, chilled noodles, snack noodles, cannedfood, canned meat and meat products, canned fish/seafood, cannedvegetables, canned tomatoes, canned beans, canned fruit, canned readymeals, canned soup, canned pasta, other canned foods, frozen food,frozen processed red meat, frozen processed poultry, frozen processedfish/seafood, frozen processed vegetables, frozen meat substitutes,frozen potatoes, oven baked potato chips, other oven baked potatoproducts, non-oven frozen potatoes, frozen bakery products, frozendesserts, frozen ready meals, frozen pizza, frozen soup, frozen noodles,other frozen food, dried food, dessert mixes, dried ready meals,dehydrated soup, instant soup, dried pasta, plain noodles, instantnoodles, cups/bowl instant noodles, pouch instant noodles, chilled food,chilled processed meats, chilled fish/seafood products, chilledprocessed fish, chilled coated fish, chilled smoked fish, chilled lunchkit, chilled ready meals, chilled pizza, chilled soup, chilled/freshpasta, chilled noodles, oils and fats, olive oil, vegetable and seedoil, cooking fats, butter, margarine, spreadable oils and fats,functional spreadable oils and fats, sauces, dressings and condiments,tomato pastes and purees, bouillon/stock cubes, stock cubes, gravygranules, liquid stocks and fonds, herbs and spices, fermented sauces,soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes,ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings,regular salad dressings, low fat salad dressings, vinaigrettes, dips,pickled products, other sauces, dressings and condiments, baby food,milk formula, standard milk formula, follow-on milk formula, toddlermilk formula, hypoallergenic milk formula, prepared baby food, driedbaby food, other baby food, spreads, jams and preserves, honey,chocolate spreads, nut-based spreads, and yeast-based spreads. Exemplarycomestible compositions also include confectioneries, bakery products,ice creams, dairy products, sweet and savory snacks, snack bars, mealreplacement products, ready meals, soups, pastas, noodles, canned foods,frozen foods, dried foods, chilled foods, oils and fats, baby foods, orspreads or a mixture thereof.

In one embodiment, the pharmaceutical composition comprises one or morecompounds of the present invention and at least one pharmaceuticallyacceptable carrier. The pharmaceutical composition includes both theprescription medications and the over-the-counter medications. Thepresent compound may or may not be the therapeutically active ingredientin the pharmaceutical composition. The pharmaceutical composition can beused by any mode of administration known to one skilled in the art,particularly by topical administration, such as application of analgesiccream to the skin surface. In general, over the counter (OTC) productand oral hygiene product generally refer to product for household and/orpersonal use which may be sold without a prescription and/or without avisit to a medical professional. Examples of the OTC products include,but are not limited to vitamins and dietary supplements; topicalanalgesics and/or anesthetic; cough, cold and allergy remedies;antihistamines and/or allergy remedies; and combinations thereof.Vitamins and dietary supplements include, but are not limited tovitamins, dietary supplements, tonics/bottled nutritive drinks,child-specific vitamins, dietary supplements, any other products of orrelating to or providing nutrition, and combinations thereof. Topicalanalgesics and/or anesthetic include any topical creams/ointments/gelsused to alleviate superficial or deep-seated aches and pains, e.g.muscle pain; teething gel; patches with analgesic ingredient; andcombinations thereof. Cough, cold and allergy remedies include, but arenot limited to decongestants, cough remedies, pharyngeal preparations,medicated confectionery, antihistamines and child-specific cough, coldand allergy remedies; and combination products. Antihistamines and/orallergy remedies include, but are not limited to any systemic treatmentsfor hay fever, nasal allergies, insect bites and stings. Examples oforal hygiene product include, but are not limited to mouth cleaningstrips, toothpaste, toothbrushes, mouthwashes/dental rinses, denturecare, mouth fresheners, mouth moisturizers, at-home teeth whiteners anddental floss.

As used herein, a “personal care composition” refers to a composition tobe directly applied to the skin, mucosal, or other surface area of thebody. Examples of personal care composition include, but are not limitedto, personal paper products, such as tissue paper, napkins, and papertowel; an oral care composition, such as; toothpaste, chewing gum,breath refresher, dentifrices, and mouthwashes; a skincare or haircarecomposition, such as sunscreen cream, sunburn lotions, shaving cream,plasters, shampoos, conditioners, face cleaners, soaps, bath oils orbath foam, antiperspirants, and deodorant; a cosmetic composition, suchas moisturizer, lip balms, foundation, etc.; an insect repellentcomposition; or an insecticide composition.

In one embodiment of the invention, the present compounds are providedin a chemesthetic concentrate formulation, e.g., suitable for subsequentprocessing to produce a ready-to-use (i.e., ready-to-serve) product. By“a chemesthetic concentrate formulation”, it is meant a formulationwhich should be reconstituted with one or more diluting medium to becomea ready-to-use composition. The term “ready-to-use composition” is usedherein interchangeably with “ingestible composition”, which denotes anysubstance that, either alone or together with another substance, can betaken by mouth whether intended for consumption or not. In oneembodiment, the ready-to-use composition includes a composition that canbe directly consumed by a human or animal. The chemesthetic concentrateformulation is typically used by mixing with or diluted by one or morediluting medium, e.g., any consumable or ingestible ingredient orproduct, to impart or modify a chemesthetic sensation to the dilutingmedium. Such a use process is often referred to as reconstitution. Thereconstitution can be conducted in a household setting or an industrialsetting. For example, a frozen fruit juice concentrate can bereconstituted with water or other aqueous medium by a consumer in akitchen to obtain the ready-to-use fruit juice beverage. In anotherexample, a mouthwash concentrate can be reconstituted with water orother aqueous medium by a manufacture in large industrial scales toproduce the ready-to-use mouthwash. Since the chemesthetic concentrateformulation has the present compound and optionally a flavoring agentand/or flavor modifying agent in a concentration higher than theready-to-use composition, the chemesthetic concentrate formulation istypically not suitable for being consumed directly withoutreconstitution. There are many benefits of using and producing achemesthetic concentrate formulation. For example, one benefit is thereduction in weight and volume for transportation as the chemestheticconcentrate formulation can be reconstituted at the time of usage by theaddition of suitable solvent, solid or liquid.

In one embodiment, the chemesthetic concentrate formulation comprises i)as chemesthetic sensation modifying ingredient, a compound of thepresent invention; ii) a carrier; and iii) optionally at least oneadjuvant. The term “as chemesthetic sensation modifying ingredient”denotes that the compound of the present invention acts as a modulatorof a chemesthetic sensation (such as, a cold or cooling sensationmodulator) in the formulation. The term “carrier” denotes a usuallyinactive accessory substance, such as solvents, binders, or other inertmedium, which is used in combination with the present compound and oneor more optional adjuvants to form the formulation. For example, wateror starch can be a carrier for a flavoring concentrate formulation. Insome embodiments, the carrier is the same as the diluting medium forreconstituting the chemesthetic concentrate formulation; and in otherembodiments, the carrier is different from the diluting medium. The term“carrier” as used herein includes, but is not limited to, ingestiblyacceptable carrier.

The term “adjuvant” denotes an additive which supplements, stabilizes,maintains, or enhances the intended function or effectiveness of theactive ingredient, such as the compound of the present invention. In oneembodiment, the at least one adjuvant comprises one or more flavoringagents. The flavoring agent may be of any flavor known to one skilled inthe art or consumers, such as the flavor of chocolate, coffee, tea,mocha, French vanilla, peanut butter, chai, or combinations thereof. Inanother embodiment, the at least one adjuvant comprises one or moresweeteners. In another embodiment, the at least one adjuvant comprisesone or more ingredients selected from the group consisting of aemulsifier, a stabilizer, an antimicrobial preservative, an antioxidant,vitamins, minerals, fats, starches, protein concentrates and isolates,salts, and combinations thereof. Examples of emulsifiers, stabilizers,antimicrobial preservatives, antioxidants, vitamins, minerals, fats,starches, protein concentrates and isolates, and salts are described inU.S. Pat. No. 6,468,576, the contents of which are hereby incorporatedby reference in its entirety for all purposes.

In one embodiment, the present chemesthetic concentrate formulation canbe in a form selected from the group consisting of liquid includingsolution and suspension, solid, foamy material, paste, gel, cream, and acombination thereof, such as a liquid containing certain amount of solidcontents. In one embodiment, the chemesthetic concentrate formulation isin form of a liquid including aqueous-based and nonaqueous-based. Thepresent chemesthetic concentrate formulation can be carbonated ornon-carbonated.

The chemesthetic concentrate formulation may further comprise a freezingpoint depressant, nucleating agent, or both as the at least oneadjuvant. The freezing point depressant is a ingestibly acceptablecompound or agent which can depress the freezing point of a liquid orsolvent to which the compound or agent is added. That is, a liquid orsolution containing the freezing point depressant has a lower freezingpoint than the liquid or solvent without the freezing point depressant.In addition to depress the onset freezing point, the freezing pointdepressant may also lower the water activity of the flavoringconcentrate formulation. The examples of the freezing point depressantinclude, but are not limited to, carbohydrates, oils, ethyl alcohol,polyol, e.g., glycerol, and combinations thereof. The nucleating agentdenotes a ingestibly acceptable compound or agent which is able tofacilitate nucleation. The presence of nucleating agent in the flavoringconcentrate formulation can improve the mouthfeel of the frozen slushesof a frozen slush and to help maintain the physical properties andperformance of the slush at freezing temperatures by increasing thenumber of desirable ice crystallization centers. Examples of nucleatingagents include, but are not limited to, calcium silicate, calciumcarbonate, titanium dioxide, and combinations thereof.

In one embodiment, the chemesthetic concentrate formulation isformulated to have a low water activity for extended shelf life. Wateractivity is the ratio of the vapor pressure of water in a formulation tothe vapor pressure of pure water at the same temperature. In oneembodiment, the chemesthetic concentrate formulation has a wateractivity of less than about 0.85. In another embodiment, thechemesthetic concentrate formulation has a water activity of less thanabout 0.80. In another embodiment, the chemesthetic concentrateformulation has a water activity of less than about 0.75.

In one embodiment, the chemesthetic concentrate formulation has thepresent compound in a concentration that is at least 2 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 5 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 10 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 15 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 20 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 30 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 40 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 50 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is at least 60 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the chemesthetic concentrate formulation has the presentcompound in a concentration that is up to 100 times of the concentrationof the compound in a ready-to-use composition.

The personal product can be provided as a textile product. Examples ofthe textile product include, but are not limited to, shirts, pants,socks, towels, and etc. The present compound can be applied to thetextile product in any suitable methods known to one skilled in the art.For example, the present compound can be associated with the textile byspin-coating, imprinting, in the form of microencapsulation, directincorporation into the textile material (e.g. extruding), covalentcoupling of suitable derivatives of the modulators (via suitablespacer/linker groups, with the help of which the molecule is reversiblyor irreversibly bonded to the packaging material).

The personal product can be provided as packaging materials. Examples ofthe packaging materials include paper and plastic wrapping, which may bein various processing forms including fibers, fabrics, and moldings. Thepresent compound can be applied to the packaging material in anysuitable methods known to one skilled in the art. For example, thepresent compound can be associated with the packaging material byspin-coating, imprinting, in the form of microencapsulation, directincorporation into the packaging material (e.g. extruding), covalentcoupling of suitable derivatives of the modulators (via suitablespacer/linker groups, with the help of which the molecule is reversiblyor irreversibly bonded to the packaging material.

The compounds of the present invention can be used for modulatingtransient receptor potential channel melastatin member 8 (TRPM8) bycontacting the receptor with a compound of the present invention. Thismodulation process can be carried out either in vitro or in vivo. In oneembodiment, the compound is a TRPM8 receptor agonist.

The compounds of the present invention can also be formulated into aprecursor of the above-described compositions. By “precursor”, it ismeant a substance or composition from which another composition, such asthose described above, is formed. For example, the present compounds maybe provided as a concentrated formulation or composition which may befurther mixed or diluted to form another composition suitable forconsumption or personal use.

The present compounds can be used to modify the chemesthetic sensationof a composition by contacting the present compounds with thecomposition to form a taste-modified composition. In one embodiment, thepresent compounds can convey or impart a cooling taste to a composition.

In one embodiment, the present invention provides a method of modulatingthe cold or cooling sensation of a composition comprising combining thecomposition with a compound of the present invention, or a salt orsolvate thereof, to form a modified composition.

In one embodiment, the present invention provides a method of inducing acold or cooling sensation in a human or animal by contacting the humanor animal with a compound of the present invention.

EXAMPLES 1.1) Biological Assay

The present compounds are useful as modulators of TRPM8. The activity ofTRPM8 can be readily monitored in cell based assays using fluorescentcalcium-sensitive dyes, membrane potential dyes, or sodium-sensitivedyes. The activity of TRPM8 can also be monitored withelectrophysiological set-ups, such as patch-clamping and two-electrodevoltage clamping. A mammalian cell line derivative which stablyexpresses TRPM8 was used in biological assays in association withtesting the present compounds with cool-tasting or -feeling properties(Servant et al. US 2007/0259354 A1 and references cited therein).Typical compound concentrations tested were 100 μM, 50 μM, 10 μM, 1 μM,and 0.5 μM. The present compounds have shown strong activity as agonistsof hTRPM8. Assay results for compounds are illustrated in Table 1 below.Specifically, the Compounds listed in Table 1.1, e.g., Compounds 1.A1 toCompounds 1.A9 are the specific compounds as described herein. Forexample, Compound 1.A1 is Example 1.1.

TABLE 1.1 hTRPM8 hTRPM8 EC50 EC50 Solubility (μM) Ratio (uM) LSB SensoryResults 1.A5 25 0.123 1.B1 10.5 0.5642 1.B2 2.1 2.8113 1.B3 36.0 0.0850580 15 uM < 45 uM WS-3  1.B4 11.4 0.4504 1.B5 7.0 0.6013 1.B6 1.3 3.45891.A9 6.1 0.6861 1.A8 7.0 0.5988 1.B7 65.2 0.0698 1.A7 8.5 0.4767 1.A652.5 0.0792 1.A4 416.0 0.0100 31 5 uM > 45 uM WS-3 1.B8 34.0 0.1284 1.B9533.0 0.0081 117 5 uM > 45 uM WS-3 1.C1 9.1 0.6552 1.C2 3.7 1.6314 1.C315.5 0.3092 1.C4 3.8 1.2538 1.C5 9.0 0.5892 1.C6 13.3 0.3987 1.C7 3.91.0666 1.C8 24.5 0.1859 1.A3 46.0 0.0870 2316 10 uM~45 uM WS-3  1.C945.0 0.0870 150 1.D1 60.5 0.0747 1.D2 60.7 0.0742 1.D3 1.7 2.3914 1.D4973.4 0.0031 792 2 uM~45 uM WS-3 1.D5 189.0 0.0240 766 5 uM~45 uM WS-31.D6 117.3 0.0440 1.A2 564.0 0.0006 94 10 uM < 45 uM WS-3  1.D7 1.05.7741 1.D8 374.0 0.0170 639 2 uM~45 uM WS-3 1.A1 100.0 0.0340 337 5uM~45 uM WS-3

1.2) Sensory Studies

Three typical sensory studies are described below each followed by atable summarizing sensory results of selected compounds of the invention(Tables 1.2 to 1.4).

Formulation:

All samples made with Low Sodium Buffer (LSB) pH˜7.1 and contain 0.1%ethanol.

General Protocol:

Compounds are rated on a 15 point line scale where 45 μM WS-3(N-Ethyl-p-menthane-3-carboxamide) is ranked as a 5 in cool intensity.In most cases our compounds are tested to determine at whatconcentration the cooling intensity is equivalent to 45 μM WS-3. In eachtest, the panelist is presented with a 0 μM control sample, a 45 μM WS-3control sample and the experimental compound sample and asked to ratethe cooling intensity of each sample. Panelists are also asked to ratebitterness. In the table below there was no significant bitternessdetected unless otherwise noted. Also, in the table below, n representsthe number of tests completed for a given experiment (# panelists×#repetitions).

Conclusions:

Panelists found 5 μM of Compound A1 was significantly more cooling than0 μM WS-3 (p<0.05) and not significantly different in cooling than 45 μMWS-3 (p>0.05). There were no significant bitter offtastes in any of thesamples (p>0.05).

TABLE 1.2 Average Cooling, n = 30 (15 Panelists × 2 rep). Tukey's Value= 0.993 (α = 0.05). Treatment Average SD St Er Tukey (5%)  0 μM WS-3 0.81.8 0.3 a 45 μM WS-3 4.4 2.4 0.4 b  5 μM Compound 1.A1 4.7 2.8 0.5 bConclusions:

Panelists found 10 μM of Compound A3 was significantly more cooling than0 μM WS-3 (p<0.05) and not significantly different in cooling than 45 μMWS-3 (p>0.05). There were no significant bitter offtastes in any of thesamples (p>0.05).

TABLE 1.3 Average Cooling, n = 28 (14 Panelists × 2 rep). Tukey's Value= 1.078 (α = 0.05). Treatment Average SD St Er Tukey (5%)  0 μM WS-3 0.91.8 0.3 a 10 μM Compound 1.A3 4.5 2.6 0.5 b 45 μM WS-3 5.4 1.7 0.3 bConclusions:

Panelists found 10 μM of compound 1.A2 was significantly more coolingthan 0 μM WS-3 (p<0.05) and significantly less cooling than 45 μM WS-3(p>0.05). There were no significant bitter offtastes in any of thesamples (p>0.05).

TABLE 1.4 Average Cooling, n = 28 (14 Panelists × 2 rep). Tukey's Value= 1.022 (α = 0.05). Treatment Average SD St Er Tukey (5%)  0 μM WS-3 0.81.6 0.3 a 10 μM Compound 1.A2 2.7 2.1 0.4 b 45 μM WS-3 4.1 2.0 0.4 c

1.3) Preparation and Examples

Standard procedures and chemical transformation and related methods arewell known to one skilled in the art, and such methods and procedureshave been described, for example, in standard references such asFiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York,N.Y., 2002; Organic Reactions, vols. 1-83, John Wiley and Sons, NewYork, N.Y., 2006; March J. and Smith M., Advanced Organic Chemistry, 6thed., John Wiley and Sons, New York, N.Y.; and Larock R. C.,Comprehensive Organic Transformations, Wiley-VCH Publishers, New York,1999. All texts and references cited herein are incorporated byreference in their entirety.

Reactions using compounds having functional groups may be performed oncompounds with functional groups that may be protected. A “protected”compound or derivatives means derivatives of a compound where one ormore reactive site or sites or functional groups are blocked withprotecting groups. Protected derivatives are useful in the preparationof the compounds of the present invention or in themselves; theprotected derivatives may be the biologically active agent. An exampleof a comprehensive text listing suitable protecting groups may be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

The general synthetic schemes for the preparation of the presentcompounds are provided in the following Schemes 1.1 to 1.4.

Example 1.A4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Ethyl 2-cyclohexyl-2-methyl-3-oxobutanoate (Compound 2)

To the 1M solution of KOt-Bu in t-BuOH (30 mmol, 30 mL) under Nitrogenatmosphere at room temperature was added dropwise slowly ethyl2-methyl-3-oxobutanoate (1 eq; 30 mmol; 4.27 mL). The reaction mixturewas stirred at room temperature for 1 hour, and then cyclohexyl iodidewas added to the resulting solution and the reaction mixture was heatedat 120° C. for 24 h. A precipitate of insoluble KI was formed during thereaction. The reaction medium was allowed to cool to room temperature,and then concentrated in vacuum. The reaction was quenched with water(25 mL) and extracted with Et₂O (3×20 ml). The organic layers werecombined, washed with, brine (40 ml), dried over MgSO₄, and concentratedin vacuum, yielding 5.2 g (77%) of ethyl2-cyclohexyl-2-methyl-3-oxobutanoate as orange-yellow oil. Crude esterwas used in the next step without further purification.

4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (Compound 3)

To the solution of ethyl 2-cyclohexyl-2-methyl-3-oxobutanoate (Compound2) (5.2 g; 23 mmol) in 20 mL of toluene, was added Hydrazine, 98% (1.2eq; 27.6 mmol; 892 uL). Reaction mixture was heated at 130° C. for 18hours with Dean-Stark adapter. The reaction medium was allowed to coolto room temperature and solvent was evaporated. The resulting residuewas purified by column chromatography (Hexane/EtOAc 20%; R_(f)=0.3)utilizing a Silicycle column (120 g) to obtain the title compound (305mg; 7%) as a yellowish crystalline solid.

4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

To the suspension of NaH (60%; 1.2 eq; 0.62 mmol; 25 mg) in 5 mL ofanhydrous DMF was added solution of4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (Compound 3) (100 mg,0.51 mmol) in 5 mL of anhydrous DMF. The reaction mixture was stirred atambient temperature for 15 minutes and then 2-Bromoacetophenone (1.1 eq;0.56 mmol; 112 uL) was added. The reaction mixture was stirred at roomtemperature for 18 hrs. Then reaction was quenched with water (15 mL)and extracted with EtOAc (3×10 mL). The organic layers were combined,washed with brine (10 mL), and dried over MgSO₄. Solvent was evaporated,and the resulting residue was purified by preparative HPLC using a 25minutes CH₃CN/H₂O gradient of 5-95% to give after evaporation ofsolvents and lyophilization the title compound (79 mg, 50% yield).

Example 1.14-cyclohexal-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(Compound B11)

To a suspension of 60% NaH (1.2 eq; 14.77 mmol; 591 mg) in 15 mL ofanhydrous DMF was added dropwise a solution of4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example 1.1a) (2.4 g,12.37 mmol) in 10 mL of anhydrous DMF. The reaction mixture was stirredat room temperature for 30 minutes and then was added dropwise asolution of 2-bromoacetophenone (1.1 eq; 13.6 mmol; 2.7 g). The reactionmixture was stirred at room temperature for 18 hrs. The reaction wasquenched with water (30 ml) and extracted with EtOAc (3×30 ml). Theorganic layers were combined, washed with brine (50 ml), and dried overMgSO₄. Solvent was evaporated, and the resulting residue was purified bypreparative HPLC using a 25 minutes CH₃CN/H₂O gradient of 5-95% to giveafter evaporation of solvents and lyophilization the4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(2.3 g) as a yellowish dense oil, which crystallized upon thoroughdrying.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.12 (s, 2H), 1.93 (s, 3H), 1.64-1.71 (m,3H), 1.51-1.59 (m, 2H), 1.45-1.48 (m, 1H), 1.14-1.27 (m, 3H), 1.18 (s,3H), 0.91-1.11 (m, 2H). MS 313 (MH⁺).

Example 1.1a 4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one

To a solution of ethyl 2-cyclohexyl-2-methyl-3-oxobutanoate (Example1.1b) (7.5 g; 33 mmol) divided into 3 vials and diluted with 20 mL ofEtOH each, was added hydrazine monohydrate (4 eq; 132.6 mmol; 6.46 mL,equally divided between all vials). Reaction mixture was heated inmicrowave at 180° C. for 8 hours (16 bars). The reaction medium wasallowed to cool to room temperature and solvent was evaporated. Theresulting residue was recrystallized from hexane to obtain the titlecompound (5.2 g; 81%) as a white crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 1.90 (s, 3H), 1.65-1.72 (m,2H), 1.55-1.60 (m, 2H), 1.44-1.48 (m, 2H), 1.21-1.30 (m, 1H), 1.10-1.18(m, 2H), 1.01-1.09 (m, 1H), 1.07 (s, 3H), 0.83-0.92 (m, 1H). MS 195(MH⁺).

Example 1.1b ethyl 2-cyclohexyl-2-methyl-3-oxobutanoate

To 1M solution of KOt-Bu in t-BuOH (100 mmol, 100 mL) under nitrogenatmosphere at room temperature was added dropwise over 10 min ethyl2-methyl-3-oxobutanoate (1 eq; 100 mmol; 14.25 mL). Reaction mixture wasstirred at 50° C. for 1 hour, and then cyclohexyl iodide (1.2 eq; 120mmol; 15.6 mL) was added to the resulting solution and reaction mixturewas heated at 120° C. for 24 h. Precipitate of insoluble KI was formedduring reaction. The reaction medium was allowed to cool to roomtemperature, and then concentrated under vacuum. The reaction wasquenched with water (25 ml) and extracted with Et₂O (3×20 ml). Theorganic layers were combined, washed with brine (40 ml), and dried overMgSO₄, and concentrated under vacuum. Crude product was purified byflash column chromatography (Hexane/EtOAc 2%; R_(f)=0.6), yielding 7.5 g(33%) of ethyl 2-cyclohexyl-2-methyl-3-oxobutanoate as a light yellowoil.

¹H NMR (400 MHz, DMSO-d₆) δ 4.09 (q, J=8.0 Hz, J=8.0 Hz, 2H), 2.07-2.12(m, 1H), 2.07 (s, 3H), 1.64-1.71 (m, 2H), 1.58-1.62 (m, 1H), 1.43-1.47(m, 1H), 1.33-1.37 (m, 1H), 1.14-1.24 (m, 2H), 1.15 (t, J=8.0 Hz, 3H),1.14 (s, 3H), 0.97-1.10 (m, 2H), 0.83-0.91 (m, 1H). MS 227 (MH⁺).

Example 1.2(+)-(S)-4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Chiral separation of4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(Example 1.1) (3.7 g) was performed on Agilent LCMS system using acolumn Chiral Pak AD-H (60 min run, 15 ml/min, Hexane/IPA 10%isocratic), retention time for title compound is 56 min. Afterevaporation of solvents and lyophilization the desired enantiomer wasobtained (1043 mg) as a yellowish glassy oil. Optical rotation wasmeasured on Perkin Elmer polarimeter, model 341. Sample was prepared in10 mg/mL EtOH. [α]²⁰ _(D)=+114.3°.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.13 (d, J=1.6 Hz, 2H), 1.93 (s, 3H),1.64-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.45-1.48 (m, 1H), 1.17-1.27 (m,2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 313 (MH⁺).

Example 1.3(−)-(R)-4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.2 starting fromof4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(Example 1.1) (3.7 g). Retention time for title compound is 34 min. Thedesired enantiomer was obtained (1322 mg) as a yellowish glassy oil.[α]²⁰ _(D)=−113.9°.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.13 (d, J=1.6 Hz, 2H), 1.93 (s, 3H),1.64-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.45-1.48 (m, 1H), 1.17-1.27 (m,2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 313 (MH⁺).

Example 1.44-cyclohexyl-1-(2-(3-hydroxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (400 mg, 2.06 mmol)and 2-bromo-1-(3-hydroxyphenyl)-ethanone (487 mg, 2.26 mmol) to obtainthe desired4-cyclohexyl-1-(2-(3-hydroxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(38.7 mg, 5%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 10.0 (bs, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.30(t, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 5.03 (d, 1.6Hz, 2H), 1.91 (s, 3H), 1.63-1.69 (m, 3H), 1.51-1.59 (m, 2H), 1.45-1.48(m, 1H), 1.17-1.27 (m, 2H), 1.13 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12(m, 2H). MS 329 (MH⁺).

Example 1.54-cyclohexyl-1-(2-(3-fluorophenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(3-fluorophenyl)-ethanone (119 mg, 0.55 mmol) to obtainthe desired4-cyclohexyl-1-(2-(3-fluorophenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(46 mg, 28%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (dt, J=7.6, 1.3 Hz, 1H), 7.78 (m, 1H),7.60 (td, J=7.9, 5.8 Hz, 1H), 7.53 (tdd, J=8.4, 2.6, 1.1 Hz, 1H), 5.17(d, J=18.0 Hz, 1H), 5.12 (d, J=18.0 Hz, 1H), 1.93 (s, 3H), 1.63-1.71 (m,3H), 1.51-1.63 (m, 2H), 1.44-1.47 (m, 1H), 1.17-1.27 (m, 2H), 1.14 (s,3H), 1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 331 (MH⁺).

Example 1.64-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (194 mg, 1 mmol) and2-bromo-1-(thiophen-3-yl)ethanone (226 mg, 1.1 mmol) to obtain thedesired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one(140.4 mg, 44%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (dd, J=1.2 Hz, J=2.8 Hz, 1H), 7.67 (dd,J=2.8 Hz, J=4.8 Hz, 1H), 7.52 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 5.00 (s,2H), 1.93 (s, 3H), 1.64-1.71 (m, 3H), 1.46-1.59 (m, 3H), 1.17-1.27 (m,2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 319 (MH⁺).

Example 1.7(+)-(S)-4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.2 starting fromof4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one(Example 1.6) (179 mg). Retention time for title compound is 39 min. Thedesired enantiomer was obtained (68.4 mg) as a white powder. [α]²⁰_(D)=+104.2°.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dd, J=1.2 Hz, J=2.8 Hz, 1H), 7.67 (dd,J=2.8 Hz, J=4.8 Hz, 1H), 7.52 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 5.00 (s,2H), 1.93 (s, 3H), 1.64-1.71 (m, 3H), 1.46-1.59 (m, 3H), 1.17-1.27 (m,2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 319 (MH⁺).

Example 1.8(−)-(R)-4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.2 starting fromof4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one(Example 1.6) (179 mg). Retention time for title compound is 20 min. Thedesired enantiomer was obtained (74.8 mg) as a white powder. [α]²⁰_(D)=−101.6°.

¹H NMR (400 MHz, DMSO-d₆) 8.61 (dd, J=1.2 Hz, J=2.8 Hz, 1H), 7.67 (dd,J=2.8 Hz, J=4.8 Hz, 1H), 7.52 (dd, J=1.2 Hz, J=5.2 Hz, 1H) 5.00 (s, 2H),1.93 (s, 3H), 1.64-1.71 (m, 3H), 1.46-1.59 (m, 3H), 1.17-1.27 (m, 2H),1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 319 (MH⁺).

Example 1.94-cyclohexyl-1-(2-(4-fluorophenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(4-fluorophenyl)-ethanone (119 mg, 0.55 mmol) to obtainthe desired4-cyclohexyl-1-(2-(4-fluorophenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(55 mg, 33%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (dd, J=5.6 Hz, J=9.2 Hz, 2H), 7.37 (t,J=9.2 Hz, 2H), 5.13 (d, J=1.6 Hz, 2H), 1.93 (s, 3H), 1.63-1.71 (m, 3H),1.51-1.59 (m, 2H), 1.45-1.48 (m, 1H), 1.17-1.27 (m, 2H), 1.14 (s, 3H),1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 331 (MH⁺).

Example 1.104-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-chloro-1-(thiophen-2-yl)ethanone (88 mg, 0.55 mmol) to obtain thedesired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1H-pyrazol-5(4H)-one(20.6 mg, 13%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.10-8.07 (m, 2H), 7.28 (dd, J=4.0 Hz, J=8.0Hz, 1H), 5.06 (s, 2H), 1.93 (s, 3H), 1.64-1.71 (m, 3H), 1.51-1.59 (m,2H), 1.46-1.49 (m, 1H), 1.17-1.27 (m, 2H), 1.14 (s, 3H), 1.11-1.17 (m,1H), 0.91-1.12 (m, 2H). MS 319 (MH⁺).

Example 1.111-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 5-(bromoacetyl)-1,3-benzo-dioxolane (134 mg, 0.55 mmol) to obtainthe desired1-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one(95.5 mg, 54%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.05(d, J=8.0 Hz, 1H), 6.13 (s, 2H), 5.03 (s, 2H), 1.93 (s, 3H), 1.64-1.71(m, 3H), 1.51-1.59 (m, 2H), 1.46-1.49 (m, 1H), 1.17-1.27 (m, 2H), 1.14(s, 3H), 1.11-1.17 (m, 1H), 0.91-1.12 (m, 2H). MS 357 (MH⁺).

Example 1.124-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (400 mg, 2.06 mmol)and 2-chloro-1-(1H-pyrrol-2-yl)ethanone (326 mg, 2.26 mmol) to obtainthe desired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one(105.8 mg, 17%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1NH), 7.16-7.07 (m, 2H), 6.20 (dd,J=3.8 Hz, J=2.4 Hz, 1H), 4.80 (s, 2H), 1.91 (s, 3H), 1.64-1.71 (m, 3H),1.51-1.59 (m, 2H), 1.46-1.49 (m, 1H), 1.17-1.27 (m, 2H), 1.12 (s, 3H),1.11-1.17 (m, 1H), 0.95-1.12 (m, 2H). MS 302 (MH⁺).

Example 1.134-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (155 mg, 0.55 mmol) toobtain the desired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)-1H-pyrazol-5(4H)-one(42.5 mg, 27%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (dd, J=2.3 Hz, J=0.8 Hz, 1H), 8.82 (dd,J=4.8 Hz, J=1.7 Hz, 1H), 8.31 (dt, J=8.0 Hz, J=1.8 Hz, 1H), 7.58 (ddd,J=8.0 Hz, J=4.8 Hz, J=0.8 Hz, 1H), 5.20 (d, J=2.0 Hz, 2H), 1.93 (s, 3H),1.63-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.44-1.47 (m, 1H), 1.17-1.27 (m,2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 314 (MH⁺).

Example 1.144-cyclohexyl-1-(2-(3-methoxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(3-methoxyphenyl)-ethanone (126 mg, 0.55 mmol) to obtainthe desired4-cyclohexyl-1-(2-(3-methoxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(75.3 mg, 44%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (ddd, J=7.6 Hz, J=1.5 Hz, J=1.0 Hz,1H), 7.50-7.41 (m, 2H), 7.23 (ddd, J=8.2 Hz, J=2.7 Hz, J=0.9 Hz, 1H),5.14 (d, J=18.0 Hz, 1H), 5.08 (d, J=18.0 Hz, 1H), 3.80 (s, 3H), 1.93 (s,3H), 1.63-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.44-1.47 (m, 1H), 1.16-1.27(m, 2H), 1.14 (s, 3H), 1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 343(MH⁺).

Example 1.154-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-2-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide (155 mg, 0.55 mmol) toobtain the desired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-2-yl)ethyl)-1H-pyrazol-5(4H)-one(13.6 mg, 9%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (ddd, J=4.8 Hz, J=1.7 Hz, J=0.9 Hz,1H), 8.04 (td, J=7.7 Hz, J=1.7 Hz, 1H), 7.96 (dt, J=7.8 Hz, J=1.2 Hz,1H), 7.72 (ddd, J=7.5 Hz, J=4.8 Hz, J=1.3 Hz, 1H), 5.22 (d, J=1.2 Hz,2H), 1.94 (s, 3H), 1.63-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.44-1.47 (m,1H), 1.17-1.28 (m, 2H), 1.16 (s, 3H), 1.11-1.17 (m, 1H), 0.89-1.12 (m,2H). MS 314 (MH⁺).

Example 1.164-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-4-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (155 mg, 0.55 mmol) toobtain the desired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(pyridin-4-yl)ethyl)-1H-pyrazol-5(4H)-one(21.7 mg, 14%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=5.6 Hz, 2H), 7.83 (d, J=6.0 Hz,2H), 5.19 (d, J=2.8 Hz, 2H), 1.93 (s, 3H), 1.63-1.71 (m, 3H), 1.51-1.59(m, 2H), 1.44-1.47 (m, 1H), 1.17-1.28 (m, 2H), 1.13 (s, 3H), 1.11-1.17(m, 1H), 0.89-1.12 (m, 2H). MS 314 (MH⁺).

Example 1.174-cyclohexyl-1-(2-(4-methoxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(4-methoxyphenyl)-ethanone (126 mg, 0.55 mmol) to obtainthe desired4-cyclohexyl-1-(2-(4-methoxyphenyl)-2-oxoethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(110 mg, 64%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz,2H), 5.05 (s, 2H), 3.83 (s, 3H), 1.92 (s, 3H), 1.63-1.71 (m, 3H),1.51-1.59 (m, 2H), 1.44-1.47 (m, 1H), 1.16-1.27 (m, 2H), 1.14 (s, 3H),1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 343 (MH⁺).

Example 1.184-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-chloro-1-(1H-pyrrol-3-yl)-ethanone (79 mg, 0.55 mmol) to obtainthe desired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-3-yl)ethyl)-1H-pyrazol-5(4H)-one(35.1 mg, 23%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (s, 1NH), 7.69 (s, 1H), 6.86 (dd,J=2.8 Hz, J=1.8 Hz, 1H), 6.47 (dd, J=2.8 Hz, J=1.5 Hz, 1H), 4.76 (s,2H), 1.91 (s, 3H), 1.64-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.46-1.49 (m,1H), 1.17-1.28 (m, 2H), 1.13 (s, 3H), 1.11-1.17 (m, 1H), 0.94-1.12 (m,2H). MS 302 (MH⁺).

Example 1.191-(2-(3-chlorophenyl)-2-oxoethyl)-4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(3-chlorophenyl)-ethanone (128 mg, 0.55 mmol) to obtainthe desired1-(2-(3-chlorophenyl)-2-oxoethyl)-4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one(56 mg, 32%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (t, J=1.8 Hz, 1H), 7.95-7.90 (m, 1H),7.74 (ddd, J=8.0 Hz, J=2.2 Hz, J=1.0 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H),5.17 (d, J=18.0 Hz, 1H), 5.10 (d, J=18.0 Hz, 1H), 1.93 (s, 3H),1.63-1.71 (m, 3H), 1.51-1.59 (m, 2H), 1.44-1.47 (m, 1H), 1.16-1.27 (m,2H), 1.13 (s, 3H), 1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 347 (MH⁺).

Example 1.204-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(m-tolyl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclohexyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (1a) (97 mg, 0.5 mmol)and 2-bromo-1-(m-tolyl)ethanone (117 mg, 0.55 mmol) to obtain thedesired4-cyclohexyl-3,4-dimethyl-1-(2-oxo-2-(m-tolyl)ethyl)-1H-pyrazol-5(4H)-one(99.3 mg, 61%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.48(d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 5.12 (d, J=18.0 Hz, 1H), 5.06(d, J=18.0 Hz, 1H), 2.36 (s, 3H), 1.93 (s, 3H), 1.63-1.71 (m, 3H),1.51-1.59 (m, 2H), 1.44-1.47 (m, 1H), 1.16-1.27 (m, 2H), 1.14 (s, 3H),1.11-1.17 (m, 1H), 0.89-1.12 (m, 2H). MS 327 (MH⁺).

Example 1.214-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one

To a suspension of NaH (60%; 1.2 eq; 1.92 mmol; 77 mg) in 3 mL ofanhydrous DMF at room temperature under N₂ atmosphere was added dropwisea solution of4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(Compound 6, Example 1.21a) (330 mg, 1.6 mmol) in 3 mL of anhydrous DMF.The reaction mixture was stirred at ambient temperature for 15 minutesand a solution of 2-bromo-1-(thiophen-3-yl)ethanone (1.1 eq; 1.76 mmol;361 mg) in 2 mL of anhydrous DMF was added dropwise. The reactionmixture was stirred at room temperature for 18 hrs. The reaction wasquenched with water (30 ml) and extracted with EtOAc (3×30 ml). Theorganic layers were combined, washed with brine (30 ml), and dried overMgSO₄. Solvent was evaporated, and the resulting residue was purified bypreparative HPLC using a 25 minutes CH₃CN/H₂O gradient of 5-95%, to giveas first-eluting the desired product4-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one(109 mg, 21%) as a white-greenish solid. NMR analysis showed thisproduct to be mostly related to exo-norbornyl enantiomer, as compared tothe literature available for NMR spectra of exo-/endo-norborneol^(i).

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (dd, J=2.8, 1.3 Hz, 1H), 7.67 (dd,J=5.1, 2.8 Hz, 1H), 7.52 (dd, J=5.1, 1.3 Hz, 1H), 5.04 (d, J=18.0 Hz,1H), 4.98 (d, J=18.0 Hz, 1H), 2.38 (bs, 1H), 2.10 (bs, 1H), 1.91 (s,3H), 1.62 (t, J=8.0 Hz, 1H), 1.43-1.45 (m, 2H), 1.23-1.30 (m, 2H), 1.20(s, 3H), 1.09-1.12 (m, 2H), 0.89-1.02 (m, 2H). MS 331 (MH⁺).

Example 1.21a4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

To the suspension of NaOMe (95%; 3 eq; 21.3 mmol; 1.2 g) in 50 mL ofanhydrous methanol at room temperature was added solution of methyl3-(2-benzoylhydrazinyl)-2-(bicyclo[2.2.1]heptan-2-yl)-2-methylbutanoate(Compound 5, Example 1.21b) (2.44 g, 7.09 mmol) in 5 mL of anhydrousmethanol. The reaction mixture was heated at 100° C. for 18 h. Amberlite(H⁺) resin was added to the reaction mixture until a clear solution andpH=4 were obtained. The resin was filtered off, washed with MeOH and theresulting solution was concentrated in vacuum. The residue was purifiedby column chromatography (DCM/EtOAc 20%; R_(f)=0.5) to obtain the titlecompound (438 mg; 30%) as a white powder, mixture of 2 isomers.

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 2.26 (bs, 0.5H), 2.15 (bs,0.5H), 2.08 (bs, 0.5H), 1.93-1.97 (m, 0.5H), 1.87 (s, 1.5H), 1.85 (s,1.5H), 1.62 (bs, 0.5H), 1.52-1.59 (m, 1H), 1.35-1.44 (m, 2H), 1.21-1.30(m, 2H), 1.10 (s, 1.5H), 1.05-1.12 (m, 2H), 0.98 (s, 1.5H), 0.95 (d,J=8.0 Hz, 0.5H), 0.86 (d, J=8.0 Hz, 0.5H), 0.74-0.77 (m, 0.5H). MS 207(MH⁺).

Example 1.21b Methyl3-(2-benzoylhydrazinyl)-2-(bicyclo[2.2.1]heptan-2-yl)-2-methylbutanoate

To a solution of benzohydrazide (50 mmol, 6.8 g) in 50 mL of EtOH wasadded acetaldehyde (1.1 eq, 55 mmol, 3.1 mL) and the reaction mixturewas stirred at room temperature for 2 h. The precipitated product wasfiltered off, washed with cold EtOH and dried in vacuum to affordN′-ethylidenebenzohydrazide (4 g, 50% yield) which was used furthercrude.

To a suspension of N′-ethylidenebenzohydrazide (1.5 g, 9.2 mmol) andscandium (III) triflate (0.1 eq, 0.92 mmol, 453 mg) in 20 mL ofanhydrous acetonitrile at −20° C. was added dropwise a solution of(2-(bicyclo[2.2.1]heptan-2-yl)-1-methoxyprop-1-enyloxy)trimethylsilane(Compound 4, Example 1.21c) (1.5 eq, 13.85 mmol, 3.5 g) in 5 mL ofanhydrous acetonitrile. The reaction mixture was stirred at −20° C. for2 h, warmed to room temperature and stirred for 18 hours. The reactionwas quenched with saturated NaHCO₃ solution (50 ml) and extracted withEtOAc (3×30 ml). The organic layers were combined, washed with brine (40ml), dried over MgSO₄ and concentrated under vacuum. The resultingresidue was purified by column chromatography (Hexane/EtOAc 20%;R_(f)=0.5) to obtain the title compound (2.4 g; 77%) as a white powder,mixture of four isomers.

¹H NMR (400 MHz, DMSO-d₆) δ 9.96-9.93 (m, 0.5NH), 9.91-9.88 (m, 0.5NH),7.91-7.72 (m, 2H), 7.57-7.34 (m, 3H), 5.01 (t, J=7.6 Hz, 0.25H), 4.94(t, J=7.6 Hz, 0.25H), 4.85 (t, J=7.6 Hz, 0.25H), 4.80 (t, J=7.6 Hz,0.25H), 3.57 (s, 0.75H), 3.56 (s, 0.75H), 3.55 (s, 0.75H), 3.53 (s,0.75H), 3.40-3.18 (m, 1H), 2.16 (bs, 0.5H), 2.11 (bs, 1H), 2.05-1.97 (m,0.75H), 1.88 (t, J=7.8 Hz, 0.25H), 1.78 (t, J=8.0 Hz, 0.25H), 1.64 (t,J=7.7 Hz, 0.25H), 1.37-1.52 (m, 3H), 1.20-1.37 (m, 2H), 1.17 (s, 0.75H),1.15-1.04 (m, 3H), 1.09 (s, 1.5H), 1.05 (s, 0.75H), 1.03-0.90 (m, 3H).MS 343 (MH⁺).

Example 1.21c(2-(bicyclo[2.2.1]heptan-2-yl)-1-methoxyprop-1-enyloxy)trimethylsilane

To a solution of diisopropylamine (23 mmol, 3.2 mL) in 20 mL ofanhydrous THF at −20° C. under nitrogen atmosphere was added dropwiseover 5 min 2.5M solution of n-butyllitium in hexane (23 mmol, 9.2 mL).The mixture was stirred for 15 min, and a solution of methyl2-(bicyclo[2.2.1]heptan-2-yl)propanoate (3) (22.7 mmol, 4.13 g) inanhydrous THF (5 mL) was added. The reaction mixture was stirred at −20°C. for 1 h, and trimethylsilyl chloride (99%, 2.5 eq, 57.5 mmol, 7.3 mL)was added dropwise. The reaction mixture was slowly warmed up to roomtemperature and stirred for 18 hours. The formed precipitate wasfiltered off, filtrate was concentrated under vacuum, washed withdiethyl ether and more precipitate was filtered off. The final solutionwas concentrated and dried under vacuum to give(2-(bicyclo[2.2.1]heptan-2-yl)-1-methoxyprop-1-enyloxy)trimethylsilane(5.5 g, 94%) as a yellow oil, mixture of E-/Z-isomers which was usedfurther crude.

¹H NMR (400 MHz, CDCl₃) δ 3.28 (s, 3H), 2.33 (t, J=8.0 Hz, 0.7H), 2.21(t, J=7.2 Hz, 0.3H), 2.01 (bs, 1H), 1.79 (bs, 1H), 1.31 (s, 1H), 1.27(s, 2H), 1.21-1.28 (m, 4H), 0.96-1.12 (m, 2H), 0.87-0.91 (m, 2H), 0.01(s, 3H), 0.00 (s, 6H).

Example 1.21d Methyl 2-(bicyclo[2.2.1]heptan-2-yl)propanoate

To a solution of methyl 2-(bicyclo[2.2.1]-heptan-2-yl)acetate (Example1.21e) (6 g, 35.7 mmol) in 50 mL of anhydrous THF at −78° C. undernitrogen atmosphere was added dropwise 1M solution of LiHMDS in THF(1.15 eq, 41 mmol, 41 mL). The reaction mixture was stirred at −78° C.for 1 h, and iodomethane (1.2 eq, 42.8 mmol, 2.6 mL) was added. Thereaction mixture was slowly warmed up to room temperature and stirredfor 18 h. The reaction was quenched with water (50 ml) and extractedwith EtOAc (3×30 ml). The organic layers were combined, washed withbrine (40 ml), dried over MgSO₄ and concentrated under vacuum. Theresulting residue was purified by column chromatography (Hexane/EtOAc2%; R_(f)=0.5) to obtain the title compound (4.13 g; 64%) as a lightyellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 3.54 (s, 3H), 2.12 (bs, 1H), 1.99-2.03 (m,1H), 1.78 (bs, 1H), 1.30-1.39 (m, 4H), 1.18-1.21 (m, 1H), 0.97-1.06 (m,4H), 0.92 (d, J=7.2 Hz, 3H). MS 183 (MH⁺).

Example 1.21e Methyl 2-(bicyclo[2.2.1]heptan-2-yl)acetate

In a 250 ml round bottom flask were placed under nitrogen atmosphere2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (5 g, 32.46 mmol), anhydrousdiethyl ether (40 mL) and methanol (10 mL) and the mixture was cooled to0° C. in an ice bath. To the mixture was then added a 2M solution of(trimethylsilyl)diazomethane in diethyl ether (2 eq., 65 mmol, 32.5 mL)dropwise. After addition was complete, the mixture was warmed to roomtemperature and stirred for 2 h. The mixture was concentrated undervacuum to afford methyl 2-(bicyclo[2.2.1]heptan-2-yl)acetate (6 g, 100%yield) which was used further crude.

¹H NMR (400 MHz, DMSO-d₆) δ 3.55 (s, 3H), 2.25 (dd, J=8.0 Hz, J=16.0 Hz,1H), 2.15 (bs, 1H), 2.10 (dd, J=8.0 Hz, J=15.2 Hz, 1H), 1.92 (bs, 1H),1.74-1.81 (m, 1H), 1.39-1.45 (m, 3H), 1.27-1.30 (m, 1H), 0.97-1.14 (m,4H). MS 169 (MH⁺).

Example 1.224-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example1.21a) (330 mg, 1.6 mmol) and 2-bromo-1-(thiophen-3-yl)ethanone (1.1 eq;1.76 mmol; 361 mg) and eluted second on preparative HPLC column, toobtain the desired4-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1H-pyrazol-5(4H)-one(99.3 mg, 61%) as a white powder. NMR analysis showed that this productmostly related to endo-norbornyl enantiomer, as compared to theliterature available NMR spectra of exo-/endo-norborneol^(ii).

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (dd, J=2.8, 1.3 Hz, 1H), 7.67 (dd,J=5.1, 2.8 Hz, 1H), 7.52 (dd, J=5.1, 1.3 Hz, 1H), 5.04 (d, J=18.0 Hz,1H), 4.98 (d, J=18.0 Hz, 1H), 2.15 (bs, 1H), 1.98-2.03 (m, 1H), 1.94 (s,3H), 1.74 (bs, 1H), 1.66 (t, J=8.0 Hz, 1H), 1.30-1.43 (m, 2H), 1.20-1.31(m, 2H), 1.08 (s, 3H), 1.09-1.12 (m, 2H), 0.87 (bd, J=9.0 Hz, 1H). MS331 (MH⁺).

Example 1.234-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example1.21a) (180 mg, 0.87 mmol) and 2-bromoacetophenone (1.1 eq; 0.96 mmol;190 mg) and eluted first on preparative HPLC column, to obtain thedesired4-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(126 mg, 39%) as a white powder. NMR analysis showed that this productmostly related to exo-norbornyl enantiomer, as compared to theliterature available NMR spectra of exo-/endo-norborneol^(iii).

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.16 (d, J=18.0 Hz, 1H), 5.09 (d, J=18.0Hz, 1H), 2.38 (bs, 1H), 2.09 (bs, 1H), 1.91 (s, 3H), 1.62 (t, J=8.0 Hz,1H), 1.43-1.45 (m, 2H), 1.21-1.32 (m, 2H), 1.21 (s, 3H), 1.09-1.12 (m,2H), 0.89-1.02 (m, 2H). MS 325 (MH⁺).

Example 1.244-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example1.21a) (180 mg, 0.87 mmol) and 2-bromoacetophenone (1.1 eq; 0.96 mmol;190 mg) and eluted second on preparative HPLC column, to obtain thedesired4-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(50 mg, 17%) as a white powder. NMR analysis showed that this productmostly related to endo-norbornyl enantiomer, as compared to theliterature available NMR spectra of exo-/endo-norborneol^(iv).

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.16 (d, J=18.0 Hz, 1H), 5.10 (d, J=18.0Hz, 1H), 2.15 (bs, 1H), 1.98-2.01 (m, 1H), 1.94 (s, 3H), 1.74 (bs, 1H),1.67 (t, J=8.0 Hz, 1H), 1.37-1.43 (m, 2H), 1.20-1.31 (m, 2H), 1.14-1.09(m, 2H), 1.09 (s, 3H), 0.88-0.85 (m, 1H). MS 325 (MH⁺).

Example 1.254-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example1.21a) (378 mg, 1.83 mmol) and 2-chloro-1-(1H-pyrrol-2-yl)ethanone (1eq; 1.83 mmol; 263 mg) and eluted first on preparative HPLC column, toobtain the desired4-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one(16.5 mg, 3%) as a white powder. NMR analysis showed that this productmostly related to exo-norbornyl enantiomer, as compared to theliterature available NMR spectra of exo-/endo-norborneol^(v).

¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1NH), 7.09-7.13 (m, 2H), 6.20 (dd,J=3.7 Hz, J=2.4 Hz, 1H), 4.89-4.77 (m, 2H), 2.40 (bs, 1H), 2.09 (bs,1H), 1.91 (s, 3H), 1.62 (t, J=8.0 Hz, 1H), 1.43-1.45 (m, 2H), 1.21-1.32(m, 2H), 1.19 (s, 3H), 1.09-1.12 (m, 2H), 0.89-1.02 (m, 2H). MS 314(MH⁺).

Example 1.264-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-(bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example1.21a) (378 mg, 1.83 mmol) and 2-chloro-1-(1H-pyrrol-2-yl)ethanone (1eq; 1.83 mmol; 263 mg) and eluted second on preparative HPLC column, toobtain the desired4-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-1H-pyrazol-5(4H)-one(17.4 mg, 3%) as a white powder. NMR analysis showed that this productmostly related to endo-norbornyl enantiomer, as compared to theliterature available NMR spectra of exo-/endo-norborneol^(vi).

¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1NH), 7.09-7.13 (m, 2H), 6.20 (dd,J=3.8 Hz, J=2.4 Hz, 1H), 4.88-4.76 (m, 2H), 2.14 (bs, 1H), 1.98-2.02 (m,1H), 1.93 (s, 3H), 1.75 (bs, 1H), 1.65 (t, J=8.0 Hz, 1H), 1.35-1.43 (m,2H), 1.24-1.31 (m, 2H), 1.09 (s, 3H), 1.09-1.14 (m, 2H), 0.87 (d, J=8.0Hz, 1H). MS 314 (MH⁺).

Example 1.274-cyclohexyl-3-ethyl-4-methyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21 starting from4-cyclohexyl-3-ethyl-4-methyl-1H-pyrazol-5(4H)-one (Example 1.27a) (104mg, 0.5 mmol) and 2-bromoacetophenone (1.1 eq; 0.55 mmol; 110 mg) toobtain the desired4-cyclohexyl-3-ethyl-4-methyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(53 mg, 32%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.16 (s, 2H), 2.27-2.33 (m, 2H), 1.63-1.72(m, 3H), 1.52-1.59 (m, 2H), 1.43 (m, 1H), 1.16-1.30 (m, 1H), 1.14 (s,3H), 1.06-1.17 (m, 3H), 1.08 (t, J=7.6 Hz, 3H), 0.90-1.02 (m, 1H). MS327 (MH⁺).

Example 1.27a 4-cyclohexyl-3-ethyl-4-methyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.21a starting frommethyl 3-(2-benzoylhydrazinyl)-2-cyclohexyl-2-methylpentanoate (Example1.27b) (1.4 g, 4 mmol) and sodium methoxide (3 eq; 12 mmol; 690 mg) toobtain the desired 4-cyclohexyl-3-ethyl-4-methyl-1H-pyrazol-5(4H)-one(462 mg, 55%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1NH), 2.22 (q, J=7.6 Hz, 2H),1.61-1.70 (m, 2H), 1.54-1.57 (m, 2H), 1.44-1.48 (m, 1H), 1.39 (m, 1H),1.24-1.27 (m, 1H), 1.06-1.14 (m, 3H), 1.08 (t, J=7.6 Hz, 3H), 1.04 (s,3H), 0.81-0.85 (m, 1H). MS 209 (MH⁺).

Example 1.27b methyl3-(2-benzoylhydrazinyl)-2-cyclohexyl-2-methylpentanoate

Prepared in a similar manner as described in Example 1.21b starting from((2-cyclohexyl-1-methoxyprop-1-en-1-yl)oxy)trimethylsilane (Example1.27c) (2.9 g, 12.35 mmol) and N′-propylidenebenzohydrazide (8.23 mmol;1.45 g) to obtain the desired methyl3-(2-benzoylhydrazinyl)2-cyclohexyl-2-methylpentanoate (462 mg, 50%) asa white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (d, J=4.0 Hz, 0.4NH), 9.92 (d, J=8.0Hz, 0.6NH), 7.80 (t, J=8.0 Hz, 2H), 7.54-7.49 (m, 1H), 7.47-7.44 (m,2H), 5.54 (t, J=8.0 Hz, 0.6NH), 4.96 (t, J=4.0 Hz, 0.4NH), 3.58 (s,0.3H), 3.57 (s, 1.0H), 3.55 (s, 1.7H), 3.23-3.20 (m, 0.4H), 3.02 (t,J=8.0 Hz, 0.6H), 1.85-1.93 (m, 1H), 1.65-1.55 (m, 4H), 1.43-1.48 (m,1H), 1.19-1.29 (m, 3H), 1.18 (s, 1.2H), 1.02-1.11 (m, 3H), 1.04 (s,1.8H), 0.96 (t, J=7.6 Hz, 3H), 0.83-0.66 (m, 1H). MS 347 (MH⁺).

Example 1.27c ((2-cyclohexyl-1-methoxyprop-1-en-1-yl)oxy)trimethylsilane

Prepared in a similar manner as described in Example 1.21c starting frommethyl 2-cyclohexylpropanoate (Example 1.27d) (5 g, 29.4 mmol) andtrimethylsilyl chloride (99%, 2.5 eq, 75 mmol; 9.46 mL) to obtain thedesired methyl((2-cyclohexyl-1-methoxyprop-1-en-1-yl)oxy)trimethylsilane (6.23 g, 87%)as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 3.43 (s, 1.8H), 3.42 (s, 1.2H), 1.65-1.74 (m,3H), 1.52-1.60 (m, 2H), 1.39 (s, 1.2H), 1.36 (s, 1.8H), 1.14-1.23 (m,5H), 1.04-1.03 (m, 1H), 0.14 (s, 3H), 0.13 (s, 6H).

Example 1.27d Methyl 2-cyclohexylpropanoate

Prepared in a similar manner as described in Example 1.21d starting frommethyl 2-cyclohexylacetate (5 g, 32 mmol) and methyl iodide (1.2 eq,38.4 mmol; 2.4 mL) to obtain the desired methyl 2-cyclohexylpropanoate(5 g, 93%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 3.56 (s, 3H), 2.19-2.22 (m, 1H), 1.40-1.67 (m,6H), 1.07-1.18 (m, 3H), 1.00 (d, J=8.0 Hz, 3H), 0.96-0.85 (m, 2H). MS171 (MH⁺).

Example 1.284-cyclopentyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-cyclopentyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example 1.28a) (100 mg,0.56 mmol) and 2-bromoacetophenone (1.1 eq; 0.67 mmol; 134 mg) to obtainthe desired4-cyclopentyl-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(43 mg, 26%) as a white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8 Hz, 2H), 5.17 (d, J=18.0 Hz, 1H), 5.11 (d, J=18.0 Hz,1H), 2.04-2.13 (m, 1H), 1.94 (s, 3H), 1.68-1.77 (m, 1H), 1.40-1.64 (m,6H), 1.19 (s, 3H), 1.02-1.11 (m, 1H). MS 299 (MH⁺). MS 299 (MH⁺).

Example 1.28a 4-cyclopentyl-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1a starting fromethyl 2-cyclopentyl-2-methyl-3-oxobutanoate (Example 1.28b) (950 mg,4.48 mmol) and hydrazine (98%, 1.2 eq; 5.37 mmol; 175 uL) to obtain thedesired 4-cyclopentyl-3,4-dimethyl-1H-pyrazol-5(4H)-one (217 mg, 27%) asa white powder.

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1NH), 1.99-2.03 (m, 1H), 1.88 (s,3H), 1.61-1.65 (m, 1H), 1.39-1.55 (m, 6H), 1.08 (s, 3H), 0.87-0.91 (m,1H). MS 181 (MH⁺).

Example 1.28b ethyl 2-cyclopentyl-2-methyl-3-oxobutanoate

Prepared in a similar manner as described in Example 1.1b starting fromethyl 2-methyl-3-oxobutanoate (2.02 mL, 14.2 mmol) and cyclopentyliodide (1.1 eq; 15.61 mmol; 3.06 g) to obtain the desired ethyl2-cyclopentyl-2-methyl-3-oxobutanoate (950 mg, 32%) as a yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 4.09 (q, J=8.0 Hz, 2H), 2.45-2.50 (m, 1H),2.07 (s, 3H), 1.43-1.67 (m, 6H), 1.23-1.29 (m, 1H), 1.17 (s, 3H), 1.15(t, J=8.0 Hz, 3H), 1.04-1.09 (m, 1H). MS 212 (MH⁺).

Example 1.293,4-dimethyl-4-(2-methylcyclopentyl)-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from3,4-dimethyl-4-(2-methylcyclopentyl)-1H-pyrazol-5(4H)-one (Example1.29a) (130 mg, 0.67 mmol) and 2-bromoacetophenone (1.2 eq; 0.8 mmol;160 mg) to obtain the desired3,4-dimethyl-4-(2-methylcyclopentyl)-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(11.6 mg, 6%) as an oily film.

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8 Hz, 2H), 5.05-5.20 (m, 2H), 2.22-2.28 (m, 0.5H),2.07-2.13 (m, 0.5H), 2.04 (s, 1H), 1.99-2.00 (m, 0.5H), 1.97 (s, 1.5H),1.94 (s, 0.5H), 1.88-1.94 (m, 0.5H), 1.40-1.81 (m, 5H), 1.22 (s, 0.75H),1.217 (s, 0.75H), 1.21 (s, 0.75H), 1.18 (s, 0.75H), 1.08-1.18 (m, 1H),0.95 (d, J=7.2 Hz, 0.5H), 0.88 (d, J=6.8 Hz, 1H), 0.66 (d, J=7.2 Hz,0.5H), 0.56 (d, J=6.8 Hz, 1H). MS 313 (MH⁺).

Example 1.29a 3,4-dimethyl-4-(2-methylcyclopentyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1a starting fromethyl 2-methyl-2-(2-methylcyclopentyl)-3-oxobutanoate (Example 1.28b)(824 mg, 3.64 mmol) and hydrazine (98%, 1.2 eq; 4.37 mmol; 141 uL) toobtain the desired3,4-dimethyl-4-(2-methylcyclopentyl)-1H-pyrazol-5(4H)-one (131 mg, 27%)as a white powder, mixture of isomers.

¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 0.5H), 10.89 (s, 0.25H), 10.86 (s,0.25H), 2.34-2.20 (m, 0.4H), 2.15-2.01 (m, 0.6H), 2.00 (s, 1H),1.99-1.93 (m, 0.8H), 1.92 (2s, 1.5H), 1.89 (s, 0.5H), 1.77-1.51 (m, 4H),1.51-1.38 (m, 1H), 1.23-1.13 (m, 1H), 1.12 (s, 1H), 1.10 (s, 1.5H), 1.09(s, 0.5H), 1.06-0.96 (m, 0.2H), 0.92 (d, J=6.8 Hz, 0.5H), 0.87 (d, J=6.6Hz, 0.5H), 0.61 (d, J=7.0 Hz, 1H), 0.53 (d, J=7.1 Hz, 1H). MS 195 (MH⁺).

Example 1.29b ethyl 2-methyl-2-(2-methylcyclopentyl)-3-oxobutanoate

Prepared in a similar manner as described in Example 1.1b starting fromethyl 2-methyl-3-oxobutanoate (2.25 mL, 15.75 mmol) and2-methylcyclopentyl 4-methylbenzenesulfonate (Example 1.29c) (1.1 eq;17.32 mmol; 4.4 g) to obtain the desired ethyl2-methyl-2-(2-methylcyclopentyl)-3-oxobutanoate (825 mg, 23%) as ayellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 4.03 (q, J=8.0 Hz, 2H), 2.29 (s, 3H),1.91-2.04 (m, 1H), 1.69-1.85 (m, 2H), 1.69 (s, 3H), 1.40-1.67 (m, 1H),1.45-1.59 (m, 3H), 1.31-1.42 (m, 1H), 1.17 (t, J=8.0 Hz, 3H), 1.95 (d,J=6.4 Hz, 3H). MS 227 (MH⁺).

Example 1.29c 2-methylcyclopentyl 4-methylbenzenesulfonate

To a solution of 2-methylcyclopentanol (4.5 g; 45 mmol) in pyridine(14.5 mL) with ice cooling was added tosyl chloride (1.1 eq., 49.5 mmol,9.43 g). The reaction mixture was stirred at room temperature for 18hours. The reaction was quenched with water (30 ml) and extracted withEtOAc (3×30 ml). The organic layers were combined, washed with brine (50ml), and dried over MgSO₄. The crude product was purified by flashcolumn chromatography (Hexane/EtOAc 20%; R_(f)=0.7), yielding 8.85 g(77%) of 2-methylcyclopentyl 4-methylbenzenesulfonate as white crystals.

¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz,2H), 4.33-4.37 (m, 1H), 2.38 (s, 3H), 1.91-1.96 (m, 1H), 1.73-1.79 (m,2H), 1.50-1.58 (m, 3H), 1.00-1.07 (m, 1H), 0.74 (d, J=6.4 Hz, 3H).

Example 1.304-(cyclohexylmethyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

To an oven-dried, N₂-flushed, round-bottom flask were added anhydrousDMF (8 mL), 4-(cyclohexylmethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(Example 1.30a) (170.0 mg, 0.82 mmol), and at 0° C. NaH (60%, 38.0 mg,0.95 mmol). The reaction mixture was stirred for 15 minutes at roomtemperature and 2-bromo-1-phenylethanone (184.0 mg, 0.92 mmol) inanhydrous DMF (1 mL) was added dropwise at 0° C. The reaction mixturewas stirred for 15 hours at room temperature and extracted withH₂O/EtOAc (3×). Combined organic phases were washed with brine, driedover MgSO₄, and solvents were evaporated. The obtained residue wasloaded onto a SiO₂ column (25 g) and eluted with a hexanes/EtOAcgradient. The obtained product was further purified on preparative HPLCusing a 40 minutes 5-95% CH₃CN/H₂O gradient, to obtain the desiredproduct (131 mg, 49%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.97 (m, 2H), 7.74-7.65 (m, 1H), 7.56(t, J=7.7 Hz, 2H), 5.23 (d, J=18.0 Hz, 1H), 5.16 (d, J=18.0 Hz, 1H),1.98 (s, 3H), 1.64-1.46 (m, 7H), 1.22-0.97 (m, 4H), 1.15 (s, 3H),0.93-0.69 (m, 2H). MS 327 (M+H⁺).

Example 1.30a 4-(cyclohexylmethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

To an oven-dried, N₂-flushed, 15 mL pressure tube were added ethyl2-(cyclohexylmethyl)-2-methyl-3-oxobutanoate (Example 1.30b) (0.5 g,2.08 mmol), anhydrous EtOH (4 mL) and hydrazine (2 mL, 63.03 mmoL). Thepressure tube was sealed and the reaction mixture was heated at 140° C.for 16 hours. The mixture was let cool down, solvents were evaporatedand the obtained residue was loaded onto a SiO₂ column (40 g) and elutedwith a hexanes/EtOAc gradient, to obtain the desired product (338 mg,78%).

¹H NMR (400 MHz, CDCl₃) δ 8.35 (bs, NH), 2.00 (s, 3H), 1.74 (dd, J=14.3Hz, J=6.8 Hz, 1H), 1.70-1.54 (m, 5H), 1.51 (dd, J=14.3 Hz, J=5.9 Hz,1H), 1.19 (s, 3H), 1.17-0.99 (m, 4H), 0.93-0.81 (m, 2H). MS 209 (MH⁺).

Example 1.30b ethyl 2-(cyclohexylmethyl)-2-methyl-3-oxobutanoate

To an oven-dried, N₂-flushed, round-bottom flask were added 1MKO-tBu/t-BuOH (8 mL), ethyl 2-methyl-3-oxobutanoate (1 g, 6.94 mmol).The reaction medium was stirred for 1 hour at room temperature and(bromomethyl)cyclohexane (1.2 mL, 8.61 mmol) was added neat anddropwise. The reaction mixture was stirred for 25 minutes at roomtemperature, refluxed for 21 hours at 120° C., and extracted withH₂O/EtOAc (4×). Combined organic phases were washed with brine, driedover MgSO₄, and solvents were evaporated. The obtained residue wasloaded onto a SiO₂ column (80 g) and eluted with a hexanes/EtOAcgradient, to obtain the desired product (1.14 g, 68%).

¹H NMR (400 MHz, CDCl₃) δ 4.17 (q, J=7.1 Hz, 2H), 2.14 (s, 3H), 1.86(dd, J=14.4 Hz, J=6.5 Hz, 1H), 1.68 (dd, J=14.4 Hz, J=5.4 Hz, 1H),1.67-1.54 (m, 5H), 1.33 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.22-1.02 (m,4H), 1.01-0.85 (m, 2H). MS 241 (MH⁺).

Example 1.314-(cyclopentylmethyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.30 from4-(cyclopentylmethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example 1.31a)(76.4 mg, 0.39 mmol) and 2-bromo-1-phenylethanone (98.0 mg, 0.49 mmol),to obtain the desired product (45.9 mg, 37%)

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.91 (m, 2H), 7.64-7.55 (m, 1H),7.54-7.41 (m, 2H), 5.13 (d, J=20.0 Hz, 1H), 5.08 (d, J=20.0 Hz, 1H),2.03 (s, 3H), 1.93 (dd, J=14.0 Hz, J=7.1 Hz, 1H), 1.72 (dd, J=13.9 Hz,J=6.3 Hz, 1H), 1.76-1.65 (m, 2H), 1.63-1.55 (m, 2H), 1.52-1.41 (m, 3H),1.28 (s, 3H), 1.13-0.92 (m, 2H). MS 313 (MH⁺).

Example 1.31a 4-(cyclopentylmethyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.30a from ethyl2-(cyclopentylmethyl)-2-methyl-3-oxobutanoate (Example 1.31b) (277.0 mg,1.22 mmol) and hydrazine (2.0 mL, 63.03 mmol), to obtain the desiredproduct as a yellowish oil (174.0 mg, 73%). MS 195 (MH⁺).

Example 1.31b ethyl 2-(cyclopentylmethyl)-2-methyl-3-oxobutanoate

Prepared in a similar manner as described in Example 1.30b from ethyl2-methyl-3-oxobutanoate (0.5 g, 3.47 mmol) and (bromomethyl)cyclopentane(672.0 mg, 4.12 mmol), to obtain the desired product as a yellowish oil(417.4 mg, 53%).

¹H NMR (400 MHz, CDCl₃) δ 4.16 (q, J=7.2 Hz, 2H), 2.13 (s, 3H), 2.00(dd, J=14.2 Hz, J=6.7 Hz, 1H), 1.88 (dd, J=14.2 Hz, J=5.6 Hz, 1H),1.78-1.64 (m, 3H), 1.62-1.52 (m, 2H), 1.52-1.40 (m, 2H), 1.34 (s, 3H),1.25 (t, J=7.1 Hz, 3H), 1.13-0.97 (m, 2H). MS 227 (MH⁺).

Example 1.324-(2-methoxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-(2-methoxy-phenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Compound 4,Example 1.32a) (394 mg, 1.8 mmol) and 2-bromoacetophenone (1.1 eq; 1.98mmol; 394 mg) to obtain the desired4-(2-methoxy-phenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(490 mg, 81%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (d, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz,1H), 6.84 (t, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.28 (d, J=18.0 Hz,1H), 5.23 (d, J=18.0 Hz, 1H), 3.75 (s, 3H), 1.80 (s, 3H), 1.55 (s, 3H).MS 337 (MH⁺).

Example 1.32a 4-(2-methoxyphenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1a starting fromethyl 2-(2-methoxyphenyl)-2-methyl-3-oxobutanoate (Example 1.32b) (600mg, 2.4 mmol) and hydrazine monohydrate (4 eq; 9.6 mmol; 467 uL) toobtain the desired 4-(2-methoxyphenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(394 mg, 75%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1NH), 7.34 (d, J=8.0 Hz, 1H), 7.30(t, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 3.60(s, 3H), 1.58 (s, 3H), 1.42 (s, 3H). MS 219 (MH⁺).

Example 1.32b ethyl 2-(2-methoxyphenyl)-2-methyl-3-oxobutanoate

To a suspension of NaH (60%; 1.3 eq; 4.05 mmol; 162 mg) in 25 mL ofanhydrous DMF at 0° C. under nitrogen atmosphere was slowly addeddropwise ethyl 2-methyl-3-oxobutanoate (1 eq; 3.11 mmol; 444 uL). Thereaction mixture was stirred at 0° C. for 30 min, and a solution ofbis(2-methoxyphenyl)iodonium tetrafluoroborate salt (Example 1.32c) (1.3eq.; 4.05 mmol; 1.73 g) in 5 mL of anhydrous DMF was added dropwise, andthe reaction mixture was stirred at room temperature for 18 h. Thereaction was quenched with water (25 ml) and extracted with Et₂O (3×20ml). The organic layers were combined, washed with brine (40 ml), driedover MgSO₄, and concentrated under vacuum. The resulting residue waspurified by flash column chromatography (Hexane/EtOAc 5%; R_(f)=0.3) toyield 603 mg (77.5%) of ethyl2-(2-methoxyphenyl)-2-methyl-3-oxobutanoate as a yellowish oil.

¹H NMR (400 MHz, DMSO-d₆) δ 7.30 (t, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz,2H), 6.94 (t, J=8.0 Hz, 1H), 4.14 (q, J=8.0 Hz, 2H), 3.71 (s, 3H), 2.08(s, 3H), 1.52 (s, 3H), 1.15 (t, J=8.0 Hz, 3H). MS 251 (MH⁺).

Example 1.32c Bis(2-methoxyphenyl)iodonium tetrafluoroborate salt

To a solution of m-chloroperbenzoic acid (77% active oxidant; 1.11 eq.;13.2 mmol; 2.27 g) in 40 mL of anhydrous 1,2-dichloroethane at roomtemperature under N₂ atmosphere was added a solution of1-iodo-2-methoxybenzene (12 mmol; 1.56 mL) in 5 mL of anhydrous1,2-dichloroethane. The reaction mixture was placed in an 80° C.pre-heated oil bath. After 1 hour, the mixture was cooled to −78° C.,and a 0° C. mixture of BF₃OEt₂ (2.5 eq.; 30 mmol; 3.77 mL) and2-methoxyphenylboronic acid (1.11 eq.; 13.2 mmol; 2 g) dissolved in 10mL of anhydrous DCM was added dropwise via syringe. The resulting darksolution was stirred at −78° C. for 1 hour, then slowly warmed up toroom temperature and stirred for 18 h. The crude reaction mixture wasloaded on a silica plug (50 g) and eluted with DCM (200 mL) to removeunreacted ArI and m-CPBA, followed by DCM/MeOH (300 mL, 20:1) to elutethe product, leaving any boronic acid derivatives on the column. Thelatter solution was concentrated in vacuum and diethyl ether (10 mL) wasadded to the residue to induce a precipitation of salt, with any iodine(III) intermediates and BF₃ derivatives remaining in solution. The solidwas filtered off, washed with diethyl ether (2×10 mL) and then dried invacuum to give pure bis(2-methoxyphenyl)iodonium tetrafluoroborate saltas a grey powder (1.73 g, 34% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J=8.0 Hz, 2H), 7.59 (t, J=8.0 Hz,2H), 7.25 (d, J=8.0 Hz, 2H), 7.02 (t, J=8.0 Hz, 2H), 3.89 (s, 6H).

Example 1.334-(2-hydroxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

To a solution of4-(2-methoxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(Example 1.32) (490 mg; 1.46 mmol) in 6 mL of anhydrous DMF, was addedsodium ethanethiolate (5 eq; 7.3 mmol; 613 mg). The reaction mixture washeated under microwave irradiation at 180° C. for 20 min, diluted with1N HCl (15 ml) and extracted with EtOAc (3×10 ml). The organic layerswere combined, washed with brine (10 ml), and dried over MgSO₄. Solventswere evaporated, and the resulting residue was purified twice onpreparative HPLC using a 25 minutes 5-95% CH₃CN/H₂O gradient, to giveafter evaporation of solvents and lyophilization4-(2-hydroxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-oneas a white solid (81.7 mg; 19%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (bs, 10H), 8.01 (d, J=8.0 Hz, 2H), 7.68(t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.14(t, J=8.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.26(d, J=18.0 Hz, 1H), 5.05 (d, J=18.0 Hz, 1H), 1.67 (s, 3H), 1.54 (s, 3H).MS 323 (MH⁺).

Example 1.344-(4-methoxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from4-(4-methoxyphenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one (Example 1.32a)(55 mg, 0.25 mmol) and 2-bromoacetophenone (1.1 eq; 0.275 mmol; 55 mg)to obtain the desired4-(4-methoxyphenyl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one(30.2 mg, 36%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=8.0 Hz, 2H), 7.69 (t, J=8.0 Hz,1H), 7.56 (t, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz,2H), 5.28 (d, J=18.0 Hz, 1H), 5.23 (d, J=18.0 Hz, 1H), 3.74 (s, 3H),1.81 (s, 3H), 1.55 (s, 3H). MS 337 (MH⁺).

Example 1.34a 4-(4-methoxyphenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1a starting fromethyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate (Example 1.32b) (460mg, 1.84 mmol) and hydrazine monohydrate (2 eq; 3.68 mmol; 120 uL) toobtain the desired 4-(4-methoxyphenyl)-3,4-dimethyl-1H-pyrazol-5(4H)-one(300 mg, 75%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1NH), 7.02 (d, J=8.0 Hz, 2H), 6.92(d, J=8.0 Hz, 2H), 3.72 (s, 3H), 1.77 (s, 3H), 1.44 (s, 3H). MS 219(MH⁺).

Example 1.34b ethyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate

Prepared in a similar manner as described in Example 1.32b starting fromethyl 2-methyl-3-oxobutanoate (425 uL, 2.98 mmol) andbis(2-methoxyphenyl)iodonium tetrafluoroborate salt (Example 1.34c) (1.3eq; 3.05 mmol; 1.25 g) to obtain the desired ethyl2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate (465 mg, 62%) as a colorlessoily liquid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (d, J=8.0 Hz, 2H), 6.91 (d, J=8.0 Hz,2H), 4.15 (q, J=8.0 Hz, 2H), 3.73 (s, 3H), 2.03 (s, 3H), 1.64 (s, 3H),1.16 (t, J=8.0 Hz, 3H). MS 251 (MH⁺).

Example 1.34c Bis(4-methoxyphenyl)iodonium tetrafluoroborate salt

Prepared in a similar manner as described in Example 1.32c starting from4-methoxyiodobenzene (1.4 mL, 6 mmol) and (4-methoxyphenyl)boronic acid(1.1 eq, 6.6 mmol, 1 g) to obtain the desiredbis(2-methoxyphenyl)iodonium tetrafluoroborate salt (1.25 g, 49%) as agrey powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=8.0 Hz, 4H), 7.04 (d, J=8.0 Hz,4H), 3.76 (s, 6H).

Example 1.353,4-dimethyl-1-(2-oxo-2-phenylethyl)-4-phenyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1 starting from3,4-dimethyl-4-phenyl-1H-pyrazol-5(4H)-one (Example 1.35a) (94 mg, 0.5mmol) and 2-bromoacetophenone (1.1 eq; 0.55 mmol; 109 mg) to obtain thedesired3,4-dimethyl-1-(2-oxo-2-phenylethyl)-4-phenyl-1H-pyrazol-5(4H)-one (87mg, 57%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=8.0 Hz, 2H), 7.69 (t, J=8.0 Hz,1H), 7.56 (t, J=8.0 Hz, 2H), 7.41 (t, J=8.0 Hz, 2H), 7.33 (t, J=8.0 Hz,1H), 7.28 (d, J=8.0 Hz, 2H), 5.30 (d, J=18.0 Hz, 1H), 5.24 (d, J=18.0Hz, 1H), 1.82 (s, 3H), 1.59 (s, 3H). MS 307 (MH⁺).

Example 1.35a 3,4-dimethyl-4-phenyl-1H-pyrazol-5(4H)-one

Prepared in a similar manner as described in Example 1.1a starting fromethyl 2-methyl-3-oxo-2-phenylbutanoate (Example 1.35b) (1.9 g, 8.6 mmol)and hydrazine monohydrate (2 eq; 17.27 mmol; 558 uL) to obtain thedesired 3,4-dimethyl-4-phenyl-1H-pyrazol-5(4H)-one (917 mg, 57%) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1NH), 7.37 (t, J=8.0 Hz, 2H), 7.30(t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 1.78 (s, 3H), 1.48 (s, 3H).MS 189 (MH⁺).

Example 1.35b Ethyl 2-methyl-3-oxo-2-phenylbutanoate

Prepared in a similar manner as described in Example 1.32b starting fromethyl 3-oxo-2-phenylbutanoate (1.9 mL, 10 mmol) and methyl iodide (3 eq;30 mmol; 1.87 mL) to obtain the desired 2-methyl-3-oxo-2-phenylbutanoate(1.9 g, 86%) as a colorless oily liquid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (t, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz,1H), 7.25 (d, J=8.0 Hz, 2H), 4.17 (q, J=8.0 Hz, 2H), 2.05 (s, 3H), 1.67(s, 3H), 1.17 (t, J=8.0 Hz, 3H). MS 221 (MH⁺).

Example 1.364-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3,4-dimethyl-1-(2-oxo-2-phenylethyl)-1H-pyrazol-5(4H)-one

Prepared by chiral separation of example 23 using standard chiral HPLC.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=8.0 Hz, 2H), 7.67 (t, J=8.0 Hz,1H), 7.53 (t, J=8.0 Hz, 2H), 5.16 (d, J=18.0 Hz, 1H), 5.09 (d, J=18.0Hz, 1H), 2.38 (bs, 1H), 2.09 (bs, 1H), 1.91 (s, 3H), 1.62 (t, J=8.0 Hz,1H), 1.43-1.45 (m, 2H), 1.21-1.32 (m, 2H), 1.21 (s, 3H), 1.09-1.12 (m,2H), 0.89-1.02 (m, 2H). MS 325 (MH⁺).

NMR REFERENCES

-   ^(i)Abraham R. J., et al. 1H chemical shifts in NMR: Part 23, the    effect of dimethyl sulphoxide versus chloroform solvent on 1H    chemical shifts. //Magn. Reson. Chem (2006), 44, p. 491-509.-   ^(ii)Abraham R. J., et al. 1H chemical shifts in NMR: Part 23, the    effect of dimethyl sulphoxide versus chloroform solvent on 1H    chemical shifts. //Magn. Reson. Chem (2006), 44, p. 491-509.-   ^(iii)Abraham R. J., et al. 1H chemical shifts in NMR: Part 23, the    effect of dimethyl sulphoxide versus chloroform solvent on 1H    chemical shifts. //Magn. Reson. Chem (2006), 44, p. 491-509.-   ^(iv)Abraham R. J., et al. 1H chemical shifts in NMR: Part 23, the    effect of dimethyl sulphoxide versus chloroform solvent on 1H    chemical shifts. //Magn. Reson. Chem (2006), 44, p. 491-509.-   ^(v)Abraham R. J., et al. 1H chemical shifts in NMR: Part 23, the    effect of dimethyl sulphoxide versus chloroform solvent on 1H    chemical shifts. //Magn. Reson. Chem (2006), 44, p. 491-509.

2.1) Biological Assay

A cell line which stably expresses hTRPM8 was used in biological assaysin association with testing the present compounds with cool-tasting or-feeling properties. Typical compound concentrations tested were 100 μM,50 μM, 10 μM, 1 μM, and 0.5 μM. The present compounds have shownactivity as agonists of hTRPM8. Assay results for compounds areillustrated in the table below. EC₅₀ in micromoles (uM) is presented aswell as the activity relative to WS3 (an established, commerciallyavailable cooling agent). EC₅₀ ratio is determined by taking the EC₅₀ ofthe example compound and dividing it by the EC₅₀ of WS3 when screened onthe same day in the same screen. A value of 1 indicates the compound isequipotent to WS3 in the assay. A number greater than one indicates howmany times more potent the compound is in the assay relative to WS3. Itis noted that Compounds 2.A1 to 2.S6 in the table below are the Examplesdescribed in this application. For example, Compound 2.B1 is Example2.2.

EC₅₀ EC₅₀ Ratio Compound (μM) (WS3) 2.A1 0.135 54.6 2.B1 0.374 13.5 2.C10.510 9.9 2.D1 0.459 13.2 2.E1 0.898 8.0 2.F1 2.881 1.6 2.G1 4.366 1.22.H1 0.192 240.6 2.I1 3.312 1.2 2.J1 0.593 14.2 2.K1 0.074 108.0 2.L16.379 0.7 2.M1 0.321 32.5 2.N1 1.091 3.5 2.O1 0.227 20.5 2.P1 0.333 11.52.Q1 0.273 15.9 2.R1 5.471 0.7 2.S1 0.760 7.0 2.T1 7.195 0.5 2.U1 0.14039.2 2.V1 1.592 2.1 2.W1 3.357 1.0 2.X1 2.039 2.1 2.Y1 1.261 3.1 2.Z16.678 0.7 2.A2 0.253 22.1 2.B2 10.115 0.5 2.C2 0.493 12.5 2.D2 0.08785.9 2.E2 0.293 13.0 2.F2 11.712 5.4 2.G2 0.621 8.8 2.H2 0.447 10.4 2.I20.927 7.7 2.J2 0.694 3.9 2.K2 0.724 5.5 2.L2 0.547 9.1 2.M2 7.542 0.52.N2 0.294 16.5 2.O2 0.588 8.0 2.P2 0.006 2566.9 2.Q2 0.029 202.6 2.R20.866 5.4 2.S2 1.985 2.3 2.T2 2.489 2.1 2.U2 0.044 178.7 2.V2 0.053 83.52.W2 0.066 77.3 2.X2 0.084 69.7 2.Y2 0.089 54.5 2.Z2 0.096 71.5 2.A30.100 73.1 2.B3 5.279 2810.1 2.C3 0.100 49.1 2.D3 0.124 33.4 2.E3 0.12753.5 2.F3 0.138 44.0 2.G3 0.146 32.6 2.H3 0.156 34.3 2.I3 0.163 33.82.J3 0.166 32.1 2.K3 0.172 30.1 2.L3 0.182 25.9 2.M3 0.192 240.6 2.N30.205 24.1 2.O3 0.223 21.6 2.P3 0.230 38.1 2.Q3 0.233 20.3 2.R3 0.23622.8 2.S3 0.246 18.1 2.T3 0.268 22.6 2.U3 0.284 17.2 2.V3 0.286 18.62.W3 0.292 19.6 2.X3 0.305 21.9 2.Y3 0.307 15.3 2.Z3 0.381 12.5 2.A40.415 8.5 2.B4 0.506 12.5 2.C4 0.527 9.5 2.D4 0.557 7.8 2.E4 0.574 9.52.F4 0.577 8.0 2.G4 0.580 7.4 2.H4 0.625 8.2 2.I4 0.705 6.4 2.J4 0.7286.4 2.K4 0.734 5.8 2.L4 0.766 6.7 2.M4 0.783 6.6 2.N4 0.794 5.9 2.O40.807 6.0 2.P4 0.827 7.9 2.Q4 0.859 6.2 2.R4 0.945 4.6 2.S4 0.968 5.02.T4 0.971 3.5 2.U4 1.116 3.0 2.V4 1.154 3.1 2.W4 1.165 4.6 2.X4 1.2044.4 2.Y4 1.263 3.9 2.Z4 1.404 3.3 2.A5 1.640 2.1 2.B5 1.470 2.2 2.C51.484 2.5 2.D5 1.503 3.4 2.E5 1.529 2.9 2.F5 1.722 2.8 2.G5 1.836 2.62.H5 1.902 2.5 2.I5 2.024 2.5 2.J5 2.064 2.4 2.K5 2.074 2.3 2.L5 2.2222.1 2.M5 2.266 1.9 2.N5 2.461 1.9 2.O5 2.526 1.4 2.P5 2.596 1.8 2.Q53.274 1.3 2.R5 3.297 1.1 2.S5 3.365 0.9 2.T5 3.457 1.0 2.U5 3.719 0.92.V5 3.863 1.3 2.W5 3.873 1.2 2.X5 3.958 1.1 2.Y5 4.199 0.9 2.Z5 4.4121.5 2.A6 4.424 1.0 2.B6 4.429 0.8 2.C6 4.655 1.0 2.D6 5.712 0.6 2.E66.556 0.6 2.F6 6.639 0.7 2.G6 8.072 0.5 2.H6 8.191 0.8 2.I6 8.443 0.52.J6 0.0004 13841.0 2.K6 0.134 19.7 2.L6 0.152 27.5 2.M6 0.749 6.9 2.N60.089 61.9 2.O6 0.161 48.2 2.P6 0.059 84.8 2.Q6 0.231 24.4 2.R6 0.03667.3 2.S6 12.667 0.5

2.2) Sensory Studies

Sensory studies were conducted for representative compounds and theresults are summarized in the table below. The results are presentedrelative to a known concentration of WS-3.

Compound Sensory Results 2.U2 30 uM~45 uM WS-3 2.Q2 30 uM~45 uM WS-32.K3 30 uM~45 uM WS-3 2.Z2 10 uM~45 uM WS-3 2.J3 15 uM~45 uM WS-3 2.T315 uM < 45 uM WS-3 2.P3 15 uM < 45 uM WS-3 2.R3 15 uM~45 uM WS-3 2.P2 10uM~45 uM WS-3 2.J6 15 uM~45 uM WS-3 2.H1 10 uM~60 uM WS-3 2.G3 15 uM <45 uM WS-3 2.N3 15 uM < 45 uM WS-3 2.V2 10 uM~45 uM WS-3 2.A1 10 uM < 45uM WS-3 2.C1 50 uM < 45 uM WS-3 2.K1 10 uM~45 uM WS-3 2.C2 80 uM > 45 uMWS-3

A more specific detailed example of the sensory evaluation of selectedexamples are also presented below. Data generated in this fashion wasused to generate the sensory summary presented in the table above.

Line Scale test with 10 uM Compound 2.H1 in LSB at pH 7.1:

-   -   10 μM Compound 2.H1 in LSB at pH 7.1 was not significantly        different in average cool intensity from 60 μM 195001 (WS-3)        (p<0.05)    -   10 μM Compound 2.H1 in LSB and 60 μM 195001 (WS-3) in LSB at pH        7.1 were significantly higher in cool intensity than LSB        (p<0.05)

TABLE 2.1 Average cool scores, n = 10 (5 × 2 Rep) Tukey's Value = 1.14(α = 0.05), 0.98 (α = 0.1). Ave St Tukey Tukey Off-Taste Test sampleCool SD Er (5%) (10%) (x number of panelist) Low Sodium 1.4 1.7 0.5 a aBuffer (LSB) 10 μM 3.6 1.6 0.5 b b Bitter x2, Linger x2 Compound 2.H1 60μM WS-3 3.7 1.6 0.5 b b Linger x2, Tingly

2.3) Preparation and Examples

Standard procedures and chemical transformation and related methods arewell known to one skilled in the art, and such methods and procedureshave been described, for example, in standard references such asFiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York,N Y, 2002; Organic Reactions, vols. 1-83, John Wiley and Sons, New York,N.Y., 2006; March J. and Smith M., Advanced Organic Chemistry, 6th ed.,John Wiley and Sons, New York, N.Y.; and Larock R. C., ComprehensiveOrganic Transformations, Wiley-VCH Publishers, New York, 1999. All textsand references cited herein are incorporated by reference in theirentirety.

Reactions using compounds having functional groups may be performed oncompounds with functional groups that may be protected. A “protected”compound or derivatives means derivatives of a compound where one ormore reactive site or sites or functional groups are blocked withprotecting groups. Protected derivatives are useful in the preparationof the compounds of the present invention or in themselves; theprotected derivatives may be the biologically active agent. An exampleof a comprehensive text listing suitable protecting groups may be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

Synthesis of the examples of the present compounds is illustrated in thefollowing schemes and procedures. One skilled in the art can readilyderive the synthesis of the present compounds from the followingdescriptions according to the methods and principles discussed above.

Example 2.1:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione

5-(cyclohex-1-en-1-yl)-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione(Example 2.1a) (133 mg, 600 μmol) and sodium hydride (60% in mineraloil, 26 mg, 660 μmol) were placed in a 40 mL vial charged with a stirbar and dry DMF (5 mL) was added via syringe under nitrogen purge withstirring. The reaction was stirred at room temperature for 5 minutes,then 2-bromo-1-phenylethanone (119 mg, 600 μmol) was added and thereaction stirred at room temperature for 1 hour. The reaction wasquenched with sat. aq. NH₄Cl (1 mL) and diluted with water (25 mL).Sufficient NaHCO₃(s) was carefully added to achieve pH˜8. The reactionmixture was extracted with DCM (3×10 mL), dried over NaCl(s), thenMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica chromatography (10→60% EtOAc/hexanes gradient). The crude productwas further purified on reversed-phase HPLC (C₁₈, water/ACN gradients)to give the target compound, 109 mg (53% yield) as a hard, light-yellowgum. ¹H NMR (400 MHz, DMSO-d₆) δ 7.977 (d of d, J=1.5 Hz, J=8.4 Hz, 2H),7.586 (t oft, J=1.5 Hz, J=5.8 Hz, 1H), 7.474 (t oft, J=1.6 Hz, 6.2 Hz,2H), 5.625 (m, 1H), 5.252 (d, J=17.2 Hz, 1H), 5.203 (d, J=17.2 Hz, 1H),3.409 (d, J=12.8 Hz, 1H), 3.369 (d, J=12.8 Hz, 1H), 3.062 (s, 3H), 2.070(m, 2H), 1.977 (m, 2H), 1.650 (m, 2H), 1.573 (m, 2H), 1.315 (s, 3H). MS341 (MH⁺).

Example 2.1a:5-(cyclohex-1-en-1-yl)-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione

5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 2.1b) (821 mg, 2.45 mmol) was placed in a 40 mL vial anddissolved in 200 proof ethanol (2.5 mL). The solution was treated with37% HCl (2.5 mL) and stirred at room temperature for 1 hour, then heatedto 50° C. for 2 hours. Volatiles were removed in vacuo (water bath=80°C.) to give 522 mg (96% yield) of a white solid. MS 223 (MH⁺).

Example 2.1b:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dione

Ethyl2-(cyclohex-1-en-1-yl)-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoate(Example 2.1c) (1073 mg, 2.82 mmol) was placed in a 40 mL vial anddissolved in dry DMF (5 mL). KOtBu (1.0 M in THF, 2.82 mL, 2.82 mmol)was added and the reaction mixture was stirred at room temperature for 1hour. Additional KOtBu (0.846 mmol, 0.846 mL) was added and stirred 15minutes more at room temperature, then the solution was heated to 50° C.and stirred for 2 hours. The reaction mixture was cooled to roomtemperature and quenched with sat. aq. NH₄Cl (1 mL) and diluted withwater (20 mL). The aqueous phase was extracted with hexanes (3×10 mL).And the combined hexane layers were washed with water (3×5 mL) andbrine, then dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude material was purified by silica gel flash chromatography (80 g,load in hexanes, 5→30% (15 CV) EtOAc/hexanes gradient) to afford 821 mg(87% yield) of the desired product. MS 335 (MH⁺).

Example 2.1c: ethyl2-(cyclohex-1-en-1-yl)-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoate

Ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate(Example 2.1d) (1043 mg, 3.2 mmol) was placed in a 40 mL vial and bothTFA (3 mL) and DCM (3 mL) were added. The resulting solution was stirredfor one hour at room temperature. Then concentrated in vacuo. The crudematerial was partitioned between water (10 mL) and 30% ACN/DCM (10 mL),then carefully made basic with NaHCO₃. The layers were separated and theaqueous phase was extracted with 30% ACN/DCM (2×10 mL). The combinedorganic extracts were washed with brine, then dried over MgSO₄,filtered, and concentrated in vacuo. The crude amine was dissolved indry DCM (2 mL) and treated with 2-isocyanato-2,4,4-trimethylpentane (546mg, 3.52 mmol) and Et₃N (0.535 mL, 3.84 mmol) with stirring at roomtemperature for 1 hour. More 2-isocyanato-2,4,4-trimethylpentane (0.117mL, 0.64 mmol). Was added and the reaction mixture was stirred for 2hours at room temperature. The reaction was diluted with water (10 mL)and DCM (5 mL) then acidified to pH˜0 with ˜2.5 mL of 6N HCl. Theresulting aqueous phase was extracted with DCM (2×10 mL), washed withbrine, then dried over MgSO₄, filtered, and concentrated in vacuo. Ethyl2-(cyclohex-1-en-1-yl)-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoatewas purified by flash chromatography (5→30% EtOAc/hexanes gradient) toafford 1073 mg (88% yield). MS 381 (MH⁺).

Example 2.1d: ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate

Ethyl3-((tert-butoxycarbonyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate(Example 2.1e) (1068 mg, 3.43 mmol) was placed in a 40 mL vial with dryDMF (10 mL) under nitrogen, then methyl iodide (321 uL, 5.14 mmol) was.NaH (60% mineral oil, 151 mg, 3.77 mmol) was added to the solution andstirred at room temperature for 1 hour under nitrogen. The reaction wasquenched with sat. aq. NH₄Cl (1 mL), diluted with water (20 mL),extracted with DCM (3×10 mL) and the combined organic layers were washedwith brine, then dried over MgSO₄, filtered, and concentrated in vacuo.The product was Purified by silica gel flash chromatography (2→10%EtOAc/hexanes gradient) to give 1043 mg of ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoateas a colorless oil (84% yield). MS 326 (MH⁺).

Example 2.1e: ethyl3-((tert-butoxycarbonyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate

Ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate (Example 2.10 (2.073 g,10.0 mmol) was placed in a 500 mL pear flask with 200 proof ethanol (40mL), then NiCl₂ (1.296 g, 10.0 mmol) was added. generating a yellowsuspension. Next, NaBH₄ (1.135 g, 30.0 mmol) was added and the reactionmixture was stirred at room temperature, overnight. Boc anhydride (3.274g, 15.0 mmol) was added to the resulting slurry and stirred at roomtemperature for 3 hours. The reaction was partitioned with water (100mL), 10% citric acid (100 mL), and DCM (150 mL). Enough 6N HCl was thenadded to dissolve most of the nickel salts, the layers were separated,and the aqueous layer was extracted with DCM (3×50 mL). The combinedorganic layers were washed with brine, then dried over MgSO₄, filtered,and concentrated in vacuo. The product was Purified by silica gel flashchromatography (1→15% EtOAc/hexanes gradient) to give 1.379 g (44%yield) of ethyl3-((tert-butoxycarbonyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoateas a nearly colorless, thick oil. MS 312 (MH⁺).

Example 2.1f: ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate

Ethyl 2-cyano-2-cyclohexylideneacetate (Example 2.1g) (19.324 g, 100.0mmol) was placed in a 500 mL pear flask with dry DMF (100 mL) andstirred under nitrogen. KOtBu (1.0 M in THF, 110 mL, 110 mmol) was addedvia syringe with stirring. The resulting orange solution was stirred forabout 1 minute and methyl iodide (9.359 mL, 150 mmol) was added viasyringe with stirring over ˜2 minutes. The reaction was stirred at roomtemperature under nitrogen for 3 hours then quenched with sat. aq. NH₄Clsolution (100 mL), diluted with water (250 mL), and extracted withhexanes (3×250 mL). The hexane layer was washed with water (4×100 mL)and aqueous NaHSO₃ solution (1×100 mL), then dried over MgSO₄, filtered,and concentrated in vacuo to afford 19.956 g (96% yield) of ethyl2-cyano-2-(cyclohex-1-en-1-yl)propanoate as a pale yellow oil that isused without further purification (˜95% pure). (¹H NMR). ¹H NMR (400MHz, DMSO-d₆) δ 6.007 (m, 1H), 4.258 (diastereotopic q, J=7.2 Hz, 1H),4.261 (diastereotopic q, J=7.2 Hz, 1H), 2.119 (m, 2H), 2.028 (m, 2H),1.682 (s, 3H), 1.61 (m, 4H), 1.311 (t, J=7.2 Hz, 3H). MS N/A (MH⁺).

Example 2.1g: ethyl 2-cyano-2-cyclohexylideneacetate

DL-proline (5.765 g, 50.0 mmol) was dissolved in 200 proof ethanol (500mL), in a 1 liter pear flask, then ethyl 2-cyanoacetate (26.65 mL, 250.0mmol) and cyclohexanone (25.883 mL, 250.0 mmol) were added via syringewith stirring. The reaction mixture was stirred overnight at roomtemperature, then heated to 75° C. for 6 hours, then additionalcyclohexanone (12.942 mL, 125.0 mmol) was added with continued heatingat 75° C. for 1 hour. The solution was cooled to room temperature,adiluted with water (100 mL) and extracted with hexanes (1×200 mL, 1×100mL). The organic phase was then dried over MgSO₄, filtered, andconcentrated in vacuo. Purification by vacuum distillation (short path,˜0.5 mmHg, 115° C.→124° C.). gives 29.501 g (61% yield) of ethyl2-cyano-2-cyclohexylideneacetate as a pale yellow oil, (98% pure). (¹HNMR). ¹H NMR (400 MHz, DMSO-d₆) δ 4.273 (q, J=7.2 Hz, 2H), 2.988 (d, J=6Hz, 1H), 2.972 (d, J=6.4 Hz, 1H), 2.671 (d, J=6.4 Hz, 1H), 2.656 (d, J=6Hz, 1H), 1.805 (m, 2H), 1.727 (m, 2H), 1.666 (m, 2H), 1.348 (t, J=7.2Hz, 3H). MS N/A (MH⁺).

Example 2.2:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 2.2 was the minor component isolated from the preparation ofExample 2.3,5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3yl)ethyl)dihydropyrimidine-2,4(1H,3H)-dione.

The mixture of5-cyclohexyl-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione (Example2.2a) (minor) and5-(cyclohex-1-en-1-yl)-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione(Example 2.3a) (major) (204 mg, 918 μmol) and sodium hydride (60% inmineral oil, 81 mg, 2020 μmol) were placed in a 40 mL vial and dissolvedin dry DMF (5 mL) under nitrogen purge. The sample was stirred at roomtemperature for 5 minutes, then 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (258 mg, 918 μmol) was added and stirred at roomtemperature for 1 hour. The reaction was quenched with sat. aq. NH₄Cl (1mL), added water (25 mL) and NaHCO₃ (s) to ensure pH˜8. The aqueousphase was extracted with DCM (3×10 mL), dried over NaCl, then MgSO₄,filtered, and concentrated in vacuo. The product was purified by silicagel chromatography (40→100% EtOAc/hexanes gradient). Fractionscontaining products were concentrated in vacuo and purified on HPLC (3injections, 40 minute runs). The fractions containing pure products wereconcentrated in vacuo, then dried overnight in a vacuum oven at 50° C.to afford 140 mg (45% yield) of a hard, somewhat sticky, very lightyellow gum(5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3yl)ethyl)dihydropyrimidine-2,4(1H,3H)-dione,Example 2.3, and 27 mg (8.6% yield) of a hard, somewhat sticky, verylight yellow gum(5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)dihydropyrimidine-2,4(1H,3H)-dione,Example 2.2, minor component). ¹H NMR (400 MHz, DMSO-d₆) (minor) δ ¹HNMR (400 MHz, CDCl₃) δ 9.20 (dd, J=2.2, 0.7 Hz, 1H), 8.81 (dd, J=4.8,1.7 Hz, 1H), 8.24 (dt, J=8.0, 1.8 Hz, 1H), 7.45 (ddd, J=8.0, 4.8, 0.8Hz, 1H), 5.22 (d, J=17.2 Hz, 1H), 5.16 (d, J=17.1 Hz, 1H), 3.38 (d,J=12.9 Hz, 1H), 3.21 (d, J=12.9 Hz, 1H), 3.08 (s, 3H), 1.91-1.59 (m,8H), 1.35-1.22 (m, 3H), 1.18 (s, 3H), 1.16-1.00 (m, 3H). Meltingpoint=N/A. MS 344 (MH⁺). ¹H NMR (400 MHz, DMSO-d₆) (major) δ 9.205 (d ofd, J=0.8 Hz, J=2.4 Hz, 1H), 8.81 (d of d, J=1.6 Hz, J=4.8 Hz, 1H), 8.244(dt, J=2.0 Hz, J=8.0 Hz, 1H), 7.440 (ddd, J=0.8 Hz, J=4.8 Hz, J=8.0 Hz,1H), 5.631 (m, 1H), 5.244 (d, J=17.2 Hz, 1H), 5.184 (d, J=17.2 Hz, 1H),3.418 (d, J=13.2 Hz, 1H), 3.363 (d, J=13.2 Hz, 1H), 3.067 (s, 3H), 2.076(m, 2H), 1.976 (m, 2H), 1.607 (m, 4H), 1.319 (s, 3H). Melting point=N/A.MS 342 (MH⁺).

Example 2.2a:5-cyclohexyl-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione and Example2.3a:5-(cyclohex-1-en-1-yl)-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione

The mixture of5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 2.0.2b) (minor) and5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dione(3b) (major) (821 mg, 2.45 mmol) was placed in a 40 mL vial anddissolved in 200 proof ethanol (2.5 mL). The solution was treated with37% HCl (2.5 mL) and stirred at room temperature for 1 hour, then heatedto 50° C. for 2 hours. The volatiles were removed in vacuo to give 522mg (96% combined yield) of a white solid. MS 225 (MH⁺) and MS 223 (MH⁺).

Example 2.2b:5-cyclohexyl-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dioneand Example 2.3b:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2,4,4-trimethylpentan-2-yl)dihydropyrimidine-2,4(1H,3H)-dione

A mixture of ethyl2-cyclohexyl-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoate(Example 2.2c) (minor) and ethyl2-(cyclohex-1-en-1-yl)-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoate(Example 2.3c) (major) (1073 mg, 2.82 mmol) was placed in a 40 mL vialand dissolved in dry DMF (5 mL). KOtBu (1.0 M in THF, 2.82 mL, 2.82mmol) was added and stirred at room temperature for 1 hour. More KOtBu(0.846 mmol, 0.846 mL) was added and stirred a further 15 minutes atroom temperature, then heated to 50° C. and stirred for 2 hours. Thereaction was cooled to room temperature and quenched with saturatedaqueous NH₄Cl (1 mL). Added water (20 mL) and extracted with hexanes(3×10 mL). The hexanes layer was washed with water (3×5 mL), dried overNaCl, then MgSO₄, filtered, and concentrated in vacuo. The crude productwas purified by silica gel chromatography (5→30% EtOAc/hexanes gradient)affording 821 mg (87% combined yield) of the desired product. MS 337(MH⁺) and MS 335 (MH⁺).

Example 2.2c: ethyl2-cyclohexyl-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)-propanoateand Example 2.3c: ethyl2-(cyclohex-1-en-1-yl)-2-methyl-3-(1-methyl-3-(2,4,4-trimethylpentan-2-yl)ureido)propanoate

The mixture of ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-cyclohexyl-2-methylpropanoate(Example 2.2d) (minor) and ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate(Example 2.3d) (major) (1043 mg, 3.2 mmol) was placed in a 40 mL vialand TFA (3 mL) and DCM (3 mL) were added. The solution was stirred forone hour at room temperature. The volatiles were removed in vacuo, thenthe residue was partitioned between water (10 mL) and 30% ACN/DCM (10mL). The solution was carefully made basic with NaHCO₃ (s), and theaqueous layer was extracted with 30% ACN/DCM (2×10 mL). The combinedorganic extracts were dried over NaCl, then MgSO₄, filtered, andconcentrated in vacuo. The crude mixture of amines was dissolved in dryDCM (2 mL) and treated with 2-isocyanato-2,4,4-trimethylpentane (546 mg,3.52 mmol) and Et₃N (0.535 mL, 3.84 mmol) and stirred at roomtemperature for 1 hour, then more 2-isocyanato-2,4,4-trimethylpentane(0.117 mL, 0.64 mmol) was added with continued Stirring for 2 hours atroom temperature. The reaction was diluted with water (10 mL) and DCM (5mL), acidified to pH˜0 with ˜2.5 mL of 6N aqueous HCl and extracted withDCM (2×10 mL). The organic phase was dried over NaCl, then MgSO₄,filtered, and concentrated in vacuo. Purification by silica gelchromatography (5→30% EtOAc/hexanes gradient). Gave 1073 mg (88%combined yield) of the desired product. MS 383 (MH⁺) and MS 381 (MH⁺).

Example 2.2d: ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-cyclohexyl-2-methylpropanoateand 3d: ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate

A mixture of ethyl3-((tert-butoxycarbonyl)amino)-2-cyclohexyl-2-methylpropanoate (Example2.2e) (major) and ethyl3-((tert-butoxycarbonyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate(Example 2.3e) (minor) (1068 mg, 3.43 mmol) was placed in a 40 mL vialwith dry DMF (10 mL). The vial was flushed with nitrogen, then methyliodide (321 uL, 5.14 mmol) was added and stirred to effect solution. NaH(60% mineral oil, 151 mg, 3.77 mmol) was added and stirred at roomtemperature for 1 hour under nitrogen purge. The reaction was quenchedwith saturated aqueous NH₄Cl (1 mL), diluted with water (20 mL), andextracted with DCM (3×10 mL). The combined organic layers were driedover NaCl, then MgSO₄, filtered, and concentrated in vacuo. Purificationby silica gel chromatography (2→10% EtOAc/hexanes gradient) gave 1043 mgof the title compounds as a colorless oil (84% combined yield). MS 328(MH⁺) and MS 326 (MH⁺).

Example 2.2e: ethyl3-((tert-butoxycarbonyl)amino)-2-cyclohexyl-2-methylpropanoate and 3e:ethyl3-((tert-butoxycarbonyl)amino)-2-(cyclohex-1-en-1-yl)-2-methylpropanoate

Ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate (Example 2.20 (2.073 g,10.0 mmol) was placed in a 500 mL pear flask with a large stir bar. 200proof ethanol (40 mL) was added, followed by NiCl₂ (1.296 g, 10.0 mmol).The reaction was stirred to get a yellow suspension. NaBH₄ (1.135 g,30.0 mmol) was added and stirred at room temperature, capping looselywith a septum. The black precipitate was stirred overnight at roomtemperature then, Boc anhydride (3.274 g, 15.0 mmol) was added andstirred an additional 3 hours at room temperature. The mixture waspartitioned with water (100 mL), 10% aqueous citric acid (100 mL), andDCM (150 mL). Enough 6N aqueous HCl was added to dissolve most of thenickel salts and the aqueous phase was extracted with DCM (3×50 mL). Thecombined DCM layers were dried over NaCl, then MgSO₄, filtered, andconcentrated in vauco. Purification by silica gel chromatography (1→15%EtOAc/hexanes gradient) gave 1.379 g (44% yield) of a nearly colorless,thick oil. The product is an inseparable mixture of the target compoundand the C═C bond reduction product. MS 314 (MH⁺) and MS 312 (MH⁺).

Example 2.2f: ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate

Ethyl 2-cyano-2-cyclohexylideneacetate (Example 2.2g) (19.324 g, 100.0mmol) was placed in a 500 mL pear flask with a large stir bar. Dry DMF(100 mL) was added and the flask was capped with a septum, and stirredunder nitrogen. KOtBu (1.0 M in THF, 110 mL, 110 mmol) was added viasyringe with stirring. The orange solution was stirred for about 1minute, then placed the flask in a room temperature water bath and addedmethyl iodide (9.359 mL, 150 mmol) via syringe with stirring over ˜2minutes. The reaction mixture was stirred at room temperature undernitrogen for 3 hours, then quenched with saturated aqueous NH₄Clsolution (100 mL) and diluted with water (250 mL). The aqueous phase wasextracted with hexanes (3×250 mL), washed with water (4×100 mL) andaqueous NaHSO₃ solution (1×100 mL), then dried over MgSO₄, filtered, andconcentrated in vacuo affording 19.956 g (96% yield) of a light yellowoil that is ˜95% pure (¹H NMR). ¹H NMR (400 MHz, DMSO-d₆) δ 6.007 (m,1H), 4.258 (diastereotopic q, J=7.2 Hz, 1H), 4.261 (diastereotopic q,J=7.2 Hz, 1H), 2.119 (m, 2H), 2.028 (m, 2H), 1.682 (s, 3H), 1.61 (m,4H), 1.311 (t, J=7.2 Hz, 3H). MS N/A (MH⁺).

Example 2.2g: ethyl 2-cyano-2-cyclohexylideneacetate

DL-proline (5.765 g, 50.0 mmol) was placed in a 1 liter pear flask witha large stir bar. 200 proof ethanol (500 mL) was added followed by theaddition of ethyl 2-cyanoacetate (26.65 mL, 250.0 mmol) andcyclohexanone (25.883 mL, 250.0 mmol) via syringe with stirring. Theflask was capped with a yellow plug and stirred overnight at roomtemperature, then heated to 75° C. for 6 hours, Another portion ofcyclohexanone (12.942 mL, 125.0 mmol) was added with continued heatingat 75° C. for 1 hour. The reaction was cooled to room temperature, addedwater (100 mL), and extracted with hexanes (1×200 mL, 1×100 mL). Theorganic phase was dried over MgSO₄, filtered, and concentrated in vacuo.Purification by vacuum distillation on (short path, ˜0.5 mmHg, 115°C.→124° C.) gave 29.501 g (61% yield) of a very light yellow oil, 98%pure (¹H NMR). ¹H NMR (400 MHz, DMSO-d₆) δ 4.273 (q, J=7.2 Hz, 2H),2.988 (d, J=6 Hz, 1H), 2.972 (d, J=6.4 Hz, 1H), 2.671 (d, J=6.4 Hz, 1H),2.656 (d, J=6 Hz, 1H), 1.805 (m, 2H), 1.727 (m, 2H), 1.666 (m, 2H),1.348 (t, J=7.2 Hz, 3H). MS N/A (MH⁺).

Example 2.3:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared in a similar manner to Example 2.1 using2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (258 mg, 918 μmol). Gives140 mg (45% yield) of a pale yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δ9.205 (d of d, J=0.8 Hz, J=2.4 Hz, 1H), 8.81 (d of d, J=1.6 Hz, J=4.8Hz, 1H), 8.244 (d oft, J=2.0 Hz, J=8.0 Hz, 1H), 7.440 (d of d of d,J=0.8 Hz, J=4.8 Hz, J=8.0 Hz, 1H), 5.631 (m, 1H), 5.244 (d, J=17.2 Hz,1H), 5.184 (d, J=17.2 Hz, 1H), 3.418 (d, J=13.2 Hz, 1H), 3.363 (d,J=13.2 Hz, 1H), 3.067 (s, 3H), 2.076 (m, 2H), 1.976 (m, 2H), 1.607 (m,4H), 1.319 (s, 3H). MS 342 (MH⁺).

Example 2.4:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione

5-cyclohexyl-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione(Example 2.4a) (841 μmol, 325 mg) was heated in a mixture of 6N aqueousHCl and ethanol (2:1, 10 mL) at 70° C. for 6 hours. The reaction wasconcentrated to dryness and the residue purified by silica gelchromatography (5→80% EtOAc/hexanes gradient). Yield 93%. ¹H NMR (400MHz, CDCl₃) δ 7.99-7.95 (m, 2H), 7.61-7.55 (m, 1H), 7.50-7.44 (m, 2H),5.22 (d, J=17.1 Hz, 1H), 5.17 (d, J=17.1 Hz, 1H), 3.37 (d, J=12.9 Hz,1H), 3.22 (d, J=12.9 Hz, 1H), 3.08 (s, 3H), 1.90-1.75 (m, 3H), 1.76-1.60(m, 3H), 1.38-1.20 (m, 3H), 1.17 (s, 3H), 1.15-0.99 (m, 3H). MS 343(MH⁺).

Example 2.4a:5-cyclohexyl-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)dihydropyrimidine-2,4(1H,3H)-dione

Ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-cyclohexyl-2-methylpropanoate(Example 2.4c) (1000 μmol, 327 mg) was dissolved in DCM (3 mL) andtrifluoroacetic acid (3 mL) was added. The reaction was stirred at roomtemperature for 30 minutes, then volatiles were removed in vacuo and theresidue treated with saturated aqueous NaHCO₃ (10 mL) and NaHCO₃ (s) toreach pH˜8. The solution was extracted with 30% ACN/DCM (v/v) (3×10 mL),dried over NaCl, then MgSO₄, filtered, and concentrated in vacuo. Thecrude ethyl 2-cyclohexyl-2-methyl-3-(methylamino)propanoate wasdissolved in DCM (10 mL) and treated with2-isocyanato-2-phenyl-1,3-dioxolane (4b) (1000 μmol, 205 mg) andtriethylamine (1500 μmol, 209 μL) and stirred at room temperatureovernight. The mixture was diluted with DCM (10 mL) and extracted with10% aqueous citric acid solution (3×5 mL). the organic phase was driedover NaCl, then MgSO₄, filtered, and concentrated to give a thick yellowoil that was used in next step without purification. The crude ethyl2-cyclohexyl-2-methyl-3-(1-methyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)ureido)propanoate(assumed 1000 μmol) was dissolved in dry DMF and added KOtBu (1100 μmol,123 mg). The solution was stirred at room temperature overnight., thenquenched with saturated aqueous NH₄Cl (2 mL), diluted with water (25mL), and extracted with DCM (3×10 mL). The organic layers were driedover NaCl, then MgSO₄, filtered, and concentrated in vacuo. Purificationby silica gel chromatography (10→60% EtOAc/hexanes gradient) affordedthe title compound in 84% yield over 3 steps. ¹H NMR is consistent withstructure. MS 387 (MH⁺).

Example 2.4b: 2-isocyanato-2-phenyl-1,3-dioxolane

(2-phenyl-1,3-dioxolan-2-yl)methanamine (Example 2.35d) (6.0 mmol, 1075mg) was added to a 250 mL Erlenmeyer flask with a large stir bar. DCM(25 mL) and sat. NaHCO₃ (25 mL) were added and stirred at 0° C. (icebath). triphosgene (2.0 mmol, 594 mg) was added and stirred at 0° C. for1 hour. The layers were separated and extracted the aqueous layer withDCM (3×15 mL). The organic phase was dried over NaCl, then MgSO₄,filtered and concentrated in vacuo to give a yellow oil that slowlysolidifies at room temperature. ¹H NMR and IR are consistent withstructure. Gives 1094 mg (91% yield).

Example 2.4c: ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2-cyclohexyl-2-methylpropanoate

Ethyl 3-((tert-butoxycarbonyl)amino)-2-cyclohexyl-2-methylpropanoate(Example 2.4d) (5.71 mmol, 1789 mg) was dissolved in dry DMF (15 mL) ina 40 mL vial flushed with nitrogen. CH₃I (8.57 mmol, 535 μL) was addedvia syringe, followed by NaH (60% in mineral oil, 6.28 mmol, 251 mg) andstirred under nitrogen purge at room temperature for 1 hour. Thereaction was quenched with saturated aqueous NH₄Cl solution (2 mL) anddiluted with water (10 mL). The aqueous layer was extracted with DCM(3×10 mL) and the DCM layers dried over NaCl, then MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (1→20% EtOAc/hexanes gradient) to afford 1675 mg (90%yield) of the title compound. ¹H NMR is consistent with structure. MS328 (MH⁺)

Example 2.4d: ethyl3-((tert-butoxycarbonyl)amino)-2-cyclohexyl-2-methylpropanoate

NiCl₂ (7.57 mmol, 981 mg) was added to a 250 mL round-bottomed flaskwith a large stir bar. A solution of ethyl2-cyano-2-cyclohexylpropanoate (Example 2.4e) (7.57 mmol, 1585 mg)dissolved in 40 mL of ethanol (200 proof) was added to the flask. NaBH₄(22.7 mmol, 860 mg) was carefully added and stirred at room temperaturefor 1 hour. A solution of Boc₂O (11.4 mmol, 2478 mg) in EtOH (200 proof)(5 mL) was added to the reaction mixture and stirred at room temperatureovernight. The reaction was quenched with 50 mL of 10% aqueous citricacid solution, DCM (100 mL) was added and everything was transferred toa 500 mL Erlenmeyer flask. 6N HCl (100 mL) and con. HCl (37%) (20 mL)were added and the aqueous phase was extracted with DCM (2×100 mL). Thecombined organic phase was dried over NaCl, then MgSO₄, filtered, andconcentrated in vacuo. Purification of the residue by silica gelchromatography (1→20% EtOAc/hexanes gradient) gave the title compound asa thick oil that slowly solidifies at room temperature to a waxy,whitish solid. Gives 2.373 g (75% yield from Example 2.4e). ¹H NMR isconsistent with structure. MS 314 (MH⁺).

Example 2.4e: ethyl 2-cyano-2-cyclohexylpropanoate

KOtBu (11.0 mmol, 1234 mg) was placed in a 40 mL vial with a stir barand dry DMF (20 mL) and flushed with nitrogen. Ethyl2-cyano-2-cyclohexylacetate (Example 2.40 (10.0 mmol, 1953 mg) was addedvia syringe and stirred at room temperature for 2 minutes, followed byaddition of CH₃I (15.0 mmol, 936 μL) via syringe with stirring at roomtemperature overnight under nitrogen. The reaction mixture was quenchedwith saturated aqueous NH₄Cl (2 mL) and added water (60 mL) andextracted with hexanes (3×50 mL). The hexanes layers were washed withwater (5×10 mL), dried over NaCl, then MgSO₄, filtered, and concentratedin vacuo. Purification by silica gel chromatography (1→15% EtOAc/hexanesgradient). Gives 2004 mg (96% yield). ¹H NMR is consistent withstructure.

Example 2.4f: ethyl 2-cyano-2-cyclohexylacetate

KOtBu (100.0 mmol, 11.221 g) was placed in a nitrogen-flushed 500 mLpear flask fitted with a stir bar. Dry DMF (100 mL) was added, followedby ethyl 2-cyanoacetate (100.0 mmol, 10.662 mL) via syringe. Thereaction was stirred at room temperature for 5 minutes, thenbromocyclohexane (100.0 mmol, 12.214 mL) was added via syringe. Thereaction was stirred at room temperature overnight, then heated to 80°C. (2 h), 100° C. (2 h), then stirred over the weekend at roomtemperature. The reaction mixture was quenched with saturated aqueousNH₄Cl (10 mL) and diluted with water (300 mL), then extracted withhexanes (3×100 mL). The combined hexanes layer was washed with water(5×50 mL), dried over NaCl, then MgSO₄, filtered, and concentrated invacuo. Purification by silica gel chromatography (1→15% EtOAc/hexanesgradient) gave 11.307 g (58% yield) of the title compound as a lightyellow oil. ¹H NMR is consistent with structure.

Example 2.5:5-(cyclohex-1-en-1-yl)-3,5-dimethyl-1-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione

The major component from this reaction is5-(cyclohex-1-en-1-yl)-3,5-dimethyl-1-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione(Example 2.5). The minor component isolated from the reaction mixturewas5-cyclohexyl-3,5-dimethyl-1-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione(Example 2.7).

The mixture of5-(cyclohex-1-en-1-yl)-1-(2-hydroxy-2-phenylethyl)-3,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione(Example 2.5a) (major) and5-cyclohexyl-1-(2-hydroxy-2-phenylethyl)-3,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione(Example 2.7a) (minor) (237 μmol, 81 mg) in dry DMF (5 mL) was placed ina 40 mL vial and pyridinium dichromate (284 μmol, 107 mg) was added. Thereaction was stirred at room temperature for 2 days. DCM (2 mL) wasadded and stirred for 1 day, then more pyridinium dichromate (372 μmol,140 mg) was added and stirred at room temperature for 3 days. Thereaction mixture was diluted with DCM (10 mL) and treated with 1Naqueous HCl (10 mL) and water (20 mL). The aqueous layer was extractedwith DCM (2×10 mL), and the combined DCM layers were dried over NaCl,then MgSO₄, filtered, and concentrated in vacuo. Purification by silicagel chromatography (10→60% EtOAc/hexanes gradient), then by HPLC to givethe products. The major isomer(5-(cyclohex-1-en-1-yl)-3,5-dimethyl-1-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione,Example 2.5, is 19 mg (24% yield), minor isomer, Example 2.7, is 8 mg(10% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.95 (m, 2H), 7.65-7.59 (m,1H), 7.53-7.47 (m, 2H), 5.45-5.41 (m, 1H), 5.27 (d, J=17.5 Hz, 1H), 4.39(d, J=17.5 Hz, 1H), 3.52 (d, J=12.9 Hz, 1H), 3.30 (d, J=12.9 Hz, 1H),3.23 (s, 3H), 2.03-1.96 (m, 2H), 1.96-1.88 (m, 2H), 1.69-1.43 (m, 4H),1.28 (s, 3H) (major). ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.96 (m, 2H),7.65-7.59 (m, 1H), 7.54-7.47 (m, 2H), 5.01 (d, J=17.5 Hz, 1H), 4.71 (d,J=17.5 Hz, 1H), 3.36 (d, J=12.7 Hz, 1H), 3.27 (d, J=12.7 Hz, 1H), 3.20(s, 3H), 1.88-1.49 (m, 5H), 1.30-1.15 (m, 3H), 1.14 (s, 3H), 1.12-0.97(m, 3H) (minor). MS 341 (MH⁺) and 343 (MH⁺), respectively.

Example 2.5a:5-(cyclohex-1-en-1-yl)-1-(2-hydroxy-2-phenylethyl)-3,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione

A mixture ethyl2-(cyclohex-1-en-1-yl)-3-(1-(2-hydroxy-2-phenylethyl)-3-methylureido)-2-methylpropanoate(crude sample Example 2.5b) (major) and ethyl2-cyclohexyl-3-(1-(2-hydroxy-2-phenylethyl)-3-methylureido)-2-methylpropanoate(Example 2.7b) (minor) (300 μmol) was dissolved in dry DMF (4 mL). KOtBu(1.0 M in THF, 1.1 mmol, 1.1 mL) was added and stirred under nitrogenfor 24 hours. The reaction was quenched with saturated aqueous NH₄Cl (1mL) and diluted with water (25 mL), then extracted with DCM (3×10 mL),dried over NaCl, then MgSO₄, filtered, and concentrated in vacuo.Purification by silica gel chromatography (10→100% EtOAc/hexanesgradient) gave 81 mg (79% yield) of the desired product mixture. ¹H NMRis consistent with structures. MS 343 (MH⁺) and 345 (MH⁺)

Example 2.5b: Ethyl2-(cyclohex-1-en-1-yl)-3-(1-(2-hydroxy-2-phenylethyl)-3-methylureido)-2-methylpropanoate

A mixture of ethyl2-(cyclohex-1-en-1-yl)-3-(2-hydroxy-2-phenylethyl)amino)-2-methylpropanoate(crude sample from Example 2.5c) (major) and ethyl2-cyclohexyl-3-(2-hydroxy-2-phenylethyl)amino)-2-methylpropanoate(Example 2.7c) (minor) (˜1.0 mmol) was dissolved in DCM (5 mL) andtreated with 4-nitrophenyl methylcarbamate (˜1.0 mmol, 196 mg), followedby triethylamine (1.5 mmol, 209 μL) and stirred at room temperatureovernight. The volatiles were removed in vacuo, then the reaction waspartitioned between ether (20 mL) and 1N aqueous HCl (10 mL). Theorganic layer was washed with 1N aqueous HCl (10 mL) followed by 1Naqueous NaOH solution (9×5 mL), then the ether extract was dried overNaCl, then MgSO₄, filtered, and concentrated in vacuo. Purification bysilica gel chromatography (40→100% EtOAc/hexanes gradient). Gives 217mg, contaminated with some material from the previous step. The materialwas carried on to the next step without further purification. ¹H NMR isconsistent with structures. MS 389 (MH⁺) and 391 (MH⁺)

Example 2.5c: Ethyl2-(cyclohex-1-en-1-yl)-3-((2-hydroxy-2-phenylethyl)amino)-2-methylpropanoate

A mixture of ethyl 3-amino-2-(cyclohex-1-en-1-yl)-2-methylpropanoate(5d) (major) and ethyl 3-amino-2-cyclohexyl-2-methylpropanoate (Example2.7d) (minor) (1.37 mmol, 290 mg) was dissolved in ethanol (200 proof,20 mL) and 2-phenyloxirane (1.51 mmol, 172 μL) was added, followed bydiisopropylethylamine (4.11 mmol, 716 μL). The reaction was stirred atroom temperature for 30 minutes, then heated to 75° C. overnight. Thereaction was then cooled to room temperature and stirred for 24 hours.The volatiles were removed in vacuo, then the residue was partitionedbetween ether (10 mL) and water (20 mL) and acidified with 6N aqueousHCl (2 mL). The organic phase was extracted with 1N aqueous HCl (5 mL),then the combined aqueous layers were made basic with NaHCO₃ (s) andextracted with DCM (3×10 mL). The DCM layers were dried over NaCl, thenMgSO₄, filtered, and concentrated in vacuo to give 274 mg of crudeproduct. Conversion is about 50%. The product was carried on to the nextstep without further purification. ¹H NMR is consistent with structures.MS 332 (MH⁺) and 334 (MH⁺)

Example 2.5d: Ethyl 3-amino-2-(cyclohex-1-en-1-yl)-2-methylpropanoate

Ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate (5.0 mmol, 1036 mg)(Example 2.20 was dissolved in ethanol (200 proof, 20 mL) and NiCl₂ (5.0mmol, 648 mg) was added. NaBH₄ (15.0 mmol, 567 mg) was added withstirring at room temperature for 2 hours. The reaction was filteredthrough Celite, then a 0.45 μm PTFE syringe-tip filter. The mixture wasconcentrated to about 1 mL by rotary evaporation and the residue treatedwith water (50 mL) and 6N aqueous HCl (10 mL). The solution wasextracted with ether (1×50 mL), then the ether layer was washed with0.5N aqueous HCl. The combined aqueous layers were made basic withNaHCO₃ (s) and extracted with DCM (3×50 mL) (emulsifies). The emulsionwas separated from the bulk of the water layer and treated with MgSO₄until dry. The DCM extract was concentrated in vacuo to give a yellowoil. Gives 742 mg (70% yield) of a mixture of the correct product andthe C═C-bond reduced product. ¹H NMR is consistent with structures. MS212 (MH⁺) and 214 (MH⁺)

Example 2.6:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)tetrahydro-pyrimidin-2(1H)-one

To a solution of5-cyclohexenyl-1-(2-hydroxy-2-phenylethyl)-3,5-dimethyltetrahydropyrimidin-2(1H)-one(Example 2.6a) (0.12 mmol, 40 mg) in a mixture of DCM (1.5 mL)/DMF (1.5mL) was added pyridinium dichromate (0.12 mmol, 46 mg) in one portion.The reaction mixture was stirred at room temperature for 24 hrs. Anadditional 25 mg of pyridinium dichromate was added to the reactionmixture with stirring for an additional 24 hrs. When the reaction wascomplete, it was diluted in water and DCM and the organic phase wascombined and dried in vacuo. The crude material was purified bypreparative HPLC, to afford 20 mg of clean product (yield 51%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.970 (d, J=8.8 Hz, 2H), 7.549 (m, 1H), 7.442 (m,2H), 5.433 (m, 1H), 4.654 (dd, J=74 Hz &7 Hz, 2H), 3.358 (m, 2H), 3.057(m, 2H), 2.972 (s, 3H), 1.918 (m, 1H), 1.505 (m, 1H), 1.119 (s, 3H). MS327 (MH⁺).

Example 2.6a:5-cyclohexenyl-1-(2-hydroxy-2-phenylethyl)-3,5-dimethyltetrahydropyrimidin-2(1H)-one

In a solution of5-cyclohexenyl-1,5-dimethyltetrahydropyrimidin-2(1H)-one (Example 2.6b)(0.48 mmol, 100 mg) in DMF (10 mL) was added sodium hydride (60%dispersion in mineral oil, 5 eq, 2.4 mmol, 96 mg). After stirring atroom temperature for 5 mins, styrene oxide (0.96 mmol, 108 ul) was addedto the reaction mixture and the mixture was microwaved at 180° C. for 40mins, then quenched with water (10 mL). The mixture was extracted withdichloromethane (DCM) (30 mL×3), and the combined organic layers werewashed with brine, dried over MgSO4 and concentrated in vacuo. Theresulting residue was purified by mass-triggered HPLC. The fractionsionized at MS 329 were collected and concentrated. The product wasobtained as a light yellow oil 40 mg (yield 25%). MS 329 (MH⁺).

Example 2.6b: 5-cyclohexenyl-1,5-dimethyltetrahydropyrimidin-2(1H)-one

To a solution of5-(cyclohex-1-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.8a) (0.12 mmol, 40 mg) in a mixture of DCM (1.5 mL)/DMF (1.5mL) was added pyridinium dichromate (0.12 mmol, 46 mg) in one portion.The reaction mixture was stirring at room temperature for 24 hrs and anadditional 25 mg of pyridinium dichromate was added with stirring anadditional 24 hrs. When the reaction was complete by TLC, it was workedup with water and DCM and the crude material was purified by preparativeHPLC to afford 20 mg of pure product (yield 51%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.970 (d, J=8.8 Hz, 2H), 7.549 (m, 1H), 7.442 (m, 2H), 5.433(m, 1H), 4.654 (dd, J=74 Hz &7 Hz, 2H), 3.358 (m, 2H), 3.057 (m, 2H),2.972 (s, 3H), 1.918 (m, 1H), 1.505 (m, 1H), 1.119 (s, 3H). MS 327(MH⁺).

Example 2.7:5-cyclohexyl-3,5-dimethyl-1-(2-oxo-2-phenylethyl)dihydropyrimidine-2,4(1H,3H)-dione

Isolated as the minor component from the preparation of Example 2.5described above. ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.96 (m, 2H), 7.65-7.59(m, 1H), 7.54-7.47 (m, 2H), 5.01 (d, J=17.5 Hz, 1H), 4.71 (d, J=17.5 Hz,1H), 3.36 (d, J=12.7 Hz, 1H), 3.27 (d, J=12.7 Hz, 1H), 3.20 (s, 3H),1.88-1.49 (m, 5H), 1.30-1.15 (m, 3H), 1.14 (s, 3H), 1.12-0.97 (m, 3H).MS 343 (MH⁺).

Example 2.8:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

To an oven-dried 150 mL pressure tube flushed under nitrogen, were addedhexobarbital,5-(cyclohex-1-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione,(Example 2.8a) (2.7 g, 11.4 mmol) in anhydrous DMF (34 mL) and at 0° C.sodium hydride (545 mg, 13.60 mmol), and the reaction medium was stirredvigorously for a few minutes at room temperature.2-Bromo-1-phenylethanone (2.77 g, 13.92 mmol) was then added at 0° C.,the pressure tube was sealed and the reaction medium stirred for 16hours at room temperature, followed by extraction with excess H₂O/EtOAc(3×). Combined organic phases were washed with brine, dried over MgSO₄,and solvents were evaporated. The residue was first purified by flashchromatography on silica gel and eluted with a Hexane/EtOAc gradient toobtain a yellow oil that precipitated out upon standing (4.14 g). Thematerial was then re-purified by flash chromatography on silica gel andeluted again with a Hexane/EtOAc gradient to obtain a colorless oil thatprecipitated out upon standing (3.77 g), and which was taken up in EtOH3 times successively, followed by evaporation of solvents in order toeliminate all traces of undesired solvents. Finally, the obtained whiteresidue was re-dissolved in a small amount of EtOH, heated fordissolution, and let stand for recrystallisation in the refrigeratorovernight, to obtain 3.16 g (78% yield) as a fluffy white powder. ¹H NMR(400 MHz, d₆-DMSO) δ 8.09-8.04 (m, 2H), 7.76-7.70 (m, 1H), 7.62-7.56 (m,2H), 5.81-5.76 (m, 1H), 5.36 (d, J=17.7 Hz, 1H), 5.26 (d, J=17.7 Hz,1H), 3.19 (s, 3H), 2.09-1.93 (m, 3H), 1.90-1.78 (m, 1H), 1.55 (s, 3H),1.63-1.44 (m, 4H). MS 355 (MH⁺)

Example 2.8a:5-(cyclohex-1-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

The5-(cyclohex-1-en-1-yl)-6-imino-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione/5-(cyclohex-1-en-1-yl)-6-imino-3,5-dimethyldihydropyrimidine-2,4(1H,3H)-dionemixture (Example 2.8b) (67.00 mmol, 15.77 g) was placed in a 500 mLflask with a stir bar. 4 N HCl (250 mL) in 2:1 water/EtOH mixture (167mL 6 N HCl+83 mL EtOH) was added and the solution was heated to refluxfor 3 hours. The solution was cooled to room temperature and let standovernight, then diluted with water (180 mL) and the crystalline solidwas collected by filtration and washed with water. The material wasdried by suction for ˜1 hour, then on high vacuum to afford 14.41 g (91%yield) of small white crystals. ¹H-NMR of product is consistent withstructure and shows a purity >97%. MS N/A (MH⁺).

Example 2.8b:5-(cyclohex-1-en-1-yl)-6-imino-1,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione5-(cyclohex-1-en-1-yl)-6-imino-3,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione

Ethyl 2-cyano-2-(cyclohex-1-en-1-yl)propanoate (129.60 mmol, 26.87 g)(Example 2.20 and methylurea (129.60 mmol, 9.60 g) were combined in a500 mL flask, flushed with nitrogen and placed in a room temperaturewater bath. tBuOK (1.0 M in tBuOH, 142.56 mmol, 143 mL) was added to aseparate 250 mL, nitrogen-flushed flask, then the viscous tBuOK solutionwas transferred into the original solution via a large bore cannula (⅛″PTFE tubing) with continuous stirring over about 15 minutes. Thereaction was stirred at room temperature for 1 hour and a heavyprecipitate formed. The slurry was heated to 50° C. and stirredovernight under nitrogen, then cooled to room temperature, quenched with6 M HCl (60 mL) and diluted with water (600 mL). The aqueous layer wasextracted with hexanes (180 mL) and the hexanes was washed with water(150 mL). The combined aqueous layer was extracted with DCM (300 mL) andthen again with 30% ACN/DCM mixture (300 mL). The aqueous layer was madebasic with NaHCO₃ (s) and then extracted with 30% ACN/DCM (3×300 mL).The final organic extracts were dried over NaCl, then over MgSO₄,filtered, and concentrated in vacuo. This gave the product as a beigesolid, 15.77 g (52% yield). ¹H-NMR of product is consistent withstructure and shows a purity >97%. MS 236 (MH⁺).

Example 2.9:5-(cyclohex-1-en-1-yl)-1-(2-(3-methoxyphenyl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

In a small microwave tube, were added commercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (30 mg,0.127 mmol), anhydrous DMF, 2-bromo-1-(3-methoxyphenyl)ethanone (36 mg,0.157 mmol), and K₂CO₃ (21 mg, 0.152 mmol). The tube was sealed andheated at 100° C. for 6 minutes in a microwave under very high absorbingconditions. The reaction medium was extracted with H₂O/EtOAc (3×).Solvents of combined organic phases were evaporated, and the residuediluted in a minimum amount of MeOH was purified by preparative HPLCusing a 25 minutes CH₃CN/H₂O gradient as eluant, to obtain aftersolvents evaporation and drying on a lyophilizer the desired product(36.4 mg, 75%). ¹H NMR (400 MHz, d₆-Acetone) δ 7.70-7.68 (m, 1H),7.57-7.56 (m, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.26 (dd, J=2.8 Hz, J=8.0 Hz,1H), 5.84-5.83 (m, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.32 (d, J=17.6 Hz,1H), 3.89 (s, 3H), 3.26 (s, 3H), 2.10-2.03 (m, 3H), 1.98-1.90 (m, 1H),1.67-1.51 (m, 4H), 1.61 (s, 3H). MS 385 (MH⁺).

Example 2.10:5-(cyclohex-1-en-1-yl)-1-(2-(3-fluorophenyl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.9 using commercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (22 mg,0.093 mmol), 2-bromo-1-(3-fluorophenyl)ethanone (22 mg, 0.101 mmol), toobtain the desired product (20.6 mg, 59%). ¹H NMR (400 MHz, d₆-Acetone)δ 7.96 (dd, J=7.7, 0.6 Hz, 1H), 7.83-7.78 (m, 1H), 7.66 (td, J=8.1, 5.6Hz, 1H), 7.50 (td, J=8.4, 2.7 Hz, 1H), 5.85-5.80 (m, 1H), 5.42 (d,J=17.6 Hz, 1H), 5.34 (d, J=17.5 Hz, 1H), 3.26 (s, 3H), 2.12-2.01 (m,3H), 2.00-1.89 (m, 1H), 1.69-1.49 (m, 4H), 1.61 (s, 3H). MS noionization.

Example 2.11:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

To an oven-dried, N₂-flushed, 150 mL pressure tube, were added5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example2.8a) (3.0 g, 12.7 mmol) in anhydrous DMF (40 mL) and at 0° C. sodiumhydride (1.17 g, 29.3 mmol), and the reaction medium was stirredvigorously for a few minutes at room temperature.2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (4.3 g, 15.2 mmol) wasthen added at 0° C., the pressure tube was sealed and the reactionmedium stirred overnight at room temperature, followed by extractionwith excess H₂O/EtOAc (3×). Combined organic phases were washed withbrine, dried over MgSO₄, and solvents were evaporated. The residue wasfirst purified by flash chromatography on a Silicycle column (330 g) andeluted with a DCM/EtOAc gradient to obtain a yellow oil. The materialwas then re-purified by flash chromatography on a Silicycle column (120g) and eluted again with a DCM/EtOAc gradient to obtain a colourless oilwhich was taken in EtOH 3 times successively followed by evaporation ofsolvents in order to eliminate all traces of undesired solvents.Finally, the obtained oil (that precipitated out upon standing) wasre-dissolved in a small amount of EtOH, heated for dissolution, andseeded with a few flakes of desired product for recrystallisation in therefrigerator overnight, to obtain after drying on the lyophilizer thedesired product as a white fluffy powder (1.5 g, 33.2%).

¹H NMR (400 MHz, dmso) δ 9.24 (dd, J=2.3, 0.8 Hz, 1H), 8.87 (dd, J=4.8,1.7 Hz, 1H), 8.40 (ddd, J=8.0, 2.3, 1.7 Hz, 1H), 7.62 (ddd, J=8.0, 4.8,0.8 Hz, 1H), 5.80-5.76 (m, 1H), 5.41 (d, J=17.8 Hz, 1H), 5.31 (d, J=17.8Hz, 1H), 3.18 (s, 3H), 2.09-1.93 (m, 3H), 1.89-1.80 (m, 1H), 1.61-1.44(m, 4H), 1.54 (s, 3H). MS 356 (MH⁺). Melting Point: 109-111° C.Elemental analysis shows matching numbers with percentage differences of0.01 for C, 0.19 for H, and 0.07 for N.

Example 2.12:1-(2-(3-chlorophenyl)-2-oxoethyl)-5-(cyclohex-1-en-1-yl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.9 using commercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (22 mg,0.093 mmol), 2-bromo-1-(3-chlorophenyl)ethanone (24 mg, 0.103 mmol), toobtain the desired product (29.8 mg, 82%). ¹H NMR (400 MHz, d₆-Acetone)δ 8.09-8.03 (m, 2H), 7.77-7.72 (m, 1H), 7.63 (dd, J=8.0, 7.5 Hz, 1H),5.85-5.80 (m, 1H), 5.42 (d, J=17.5 Hz, 1H), 5.34 (d, J=17.2 Hz, 1H),3.26 (s, 3H), 2.11-2.01 (m, 3H), 1.99-1.89 (m, 1H), 1.68-1.50 (m, 4H),1.61 (s, 3H). MS no ionization.

Example 2.13:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)-pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.9 using commercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (20 mg,0.085 mmol), 2-chloro-1-(thiophen-2-yl)ethanone (17 mg, 0.106 mmol), toobtain the desired product (18.1 mg, 59%). ¹H NMR (400 MHz, d₆-DMSO) δ8.20 (dd, J=3.8, 1.1 Hz, 1H), 8.11 (dd, J=4.9, 1.1 Hz, 1H), 7.31 (dd,J=4.9, 3.8 Hz, 1H), 5.78-5.73 (m, 1H), 5.27 (d, J=17.5 Hz, 1H), 5.18 (d,J=17.5 Hz, 1H), 3.16 (s, 3H), 2.06-1.90 (m, 3H), 1.88-1.75 (m, 1H), 1.52(s, 3H), 1.60-1.40 (m, 4H). MS 361 (MH⁺).

Example 2.14:3-(2-(5-(cyclohex-1-en-1-yl)-3,5-dimethyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)acetyl)benzonitrile

Prepared in a similar manner to Example 2.9 using commercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (100 mg,0.423 mmol), 3-(2-bromoacetyl)benzonitrile (114 mg, 0.509 mmol), thereaction medium was also heated again for another 10 minutes at 120° C.before described work-up. The desired product was obtained (82.5 mg,51%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.56 (t, J=1.5 Hz, 1H), 8.34-8.29 (m,1H), 8.19-8.15 (m, 1H), 7.78 (t, J=7.8 Hz, 1H), 5.78-5.72 (m, 1H), 5.41(d, J=17.9 Hz, 1H), 5.31 (d, J=17.9 Hz, 1H), 3.16 (s, 3H), 2.07-1.91 (m,3H), 1.88-1.77 (m, 1H), 1.61-1.42 (m, 4H), 1.53 (s, 3H). MS noionization.

Example 2.15:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-4-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In a small oven-dried, N₂-flushed, pressure tube, were addedcommercially available5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (101.7 mg,0.430 mmol), anhydrous DMF (2 mL), NaH (46.0 mg, 1.150 mmol) and stirredfor 10 minutes, followed by 2-bromo-1-(pyridin-4-yl)ethanonehydrobromide (113.7 mg, 0.405 mmol). The tube was sealed and thereaction medium was stirred vigorously for 3.5 hours and furtherovernight. The reaction medium was extracted with H₂O/EtOAc (3×).Combined organic phases were washed with brine and dried over MgSO₄.Solvents were evaporated and the obtained residue was dissolved in aminimum amount of MeOH, filtered, and purified by Varian preparativeHPLC using a 25 minutes method and a 5-95% H₂O/MeOH gradient as eluant,to obtain after solvents evaporation and drying on a lyophilizer thedesired product (52.5 mg, 35%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.86 (dd,J=4.4, 1.7 Hz, 2H), 7.93 (dd, J=4.4, 1.7 Hz, 2H), 5.80-5.71 (m, 1H),5.39 (d, J=17.9 Hz, 1H), 5.29 (d, J=17.9 Hz, 1H), 3.18 (s, 3H),2.09-1.90 (m, 3H), 1.90-1.78 (m, 1H), 1.61-1.42 (m, 4H), 1.54 (s, 3H).MS 356 (MH⁺).

Example 2.16:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-2-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.15 using commerciallyavailable 5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(100 mg, 0.423 mmol), 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide (123mg, 0.438 mmol), to obtain the desired product (26.2 mg, 22%). ¹H NMR(400 MHz, d₆-DMSO) δ 8.83-8.77 (m, 1H), 8.07 (td, J=7.7, 1.7 Hz, 1H),8.01 (dt, J=7.8, 1.2 Hz, 1H), 7.77 (ddd, J=7.5, 4.8, 1.4 Hz, 1H),5.81-5.77 (m, 1H), 5.46 (d, J=18.2 Hz, 1H), 5.38 (d, J=18.2 Hz, 1H),3.18 (s, 3H), 2.09-1.94 (m, 3H), 1.91-1.79 (m, 1H), 1.62-1.44 (m, 4H),1.54 (s, 3H). MS 356 (MH⁺).

Example 2.17:5-(cyclohex-2-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

The suspension of5-(cyclohex-2-enyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.17a) (106 mg, 0.45 mmol), K₂CO₃ (150 mg, 1.08 mmol) and2-bromoacetophenone (100 mg, 0.5 mmol) in 5 mL of EtOH was heated undermicrowave irradiation (Biotage Personal Chemistry Emrys Optimizer) at150° C. for 10 minutes. The reaction was diluted with water (5 mL) andpurified by preparative HPLC using a 40 minutes MeOH/H₂O gradient of5-95% to give after evaporation of solvents and lyophilization 30.5 mg(20% yield) of desired product as a white fluffy powder. ¹H NMR (400MHz, DMSO-d₆) δ 8.05 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.56 (t,J=8.0 Hz, 2H), 5.76 (m, 1H), 5.62 (dd, J=8 Hz, J=68 Hz, 1H), 5.35 (dd,J=8 Hz, J=20 Hz, 1H), 5.225 (dd, J=4 Hz, J=16 Hz, 1H), 3.135 (d, J=4 Hz,3H), 2.72 (m, 1H), 1.88 (m, 2H), 1.64 (m, 2H), 1.52 (m, 1H), 1.43 (m,1H), 1.38 (d, J=16 Hz, 3H), 1.28 (m, 1H). MS 355 (MH⁺).

Example 2.17a:5-(cyclohex-2-enyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

11 g (43.3 mmol) of diethyl 2-(cyclohex-2-enyl)-2-methylmalonate(Example 2.17b) and 3.2 g (43.3 mmol) of methylurea were added to acooled solution of sodium ethoxide (from sodium, 2.5 g, and absoluteEthanol, 45 mL). Reaction mixture was heated at 100° C. for 18 h, thenconcentrated in vacuum, residue was diluted with water and acidifiedwith conc. HCl to pH=2. The obtained precipitate was filtered off, driedunder vacuum and purified by flash chromatography using a 120 gSilicycle column (Hexane/EtOAc 20% gradient; R_(f)=0.35) to give 7.08 g(69% yield) of desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s,1H), 5.74 (m, 1H), 5.47 (dd, J=8 Hz, J=16 Hz, 1H), 3.0.5 (d, J=4 Hz,3H), 2.53 (m, 1H), 1.85 (m, 2H), 1.66 (m, 1H), 1.57 (m, 1H), 1.36 (m,1H), 1.315 (d, J=4 Hz, 3H). MS 237 (MH⁺).

Example 2.17b: diethyl 2-(cyclohex-2-enyl)-2-methylmalonate

8.05 g (50 mmol) of 3-bromocyclohex-1-ene were added to a cooled mixtureof 8.7 g (50 mmol) of diethyl 2-methylmalonate and sodium ethoxide (fromsodium, 1.3 g, and absolute Ethanol, 25 mL). Reaction mixture was heatedat 100° C. for 30 min, then concentrated in vacuum, residue was dilutedwith water and product was extracted with ether. Diethyl2-(cyclohex-2-enyl)-2-methylmalonate was obtained (11 g.; 87%) as lightorange oil and used in to next step without future purification. MS 255(MH⁺).

Example 2.18:5-(cyclohex-2-en-1-yl)-1-(2-(3-methoxyphenyl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-(cyclohex-2-enyl)-1,5-dimethylpyrimi-dine-2,4,6(1H,3H,5H)-trione(Example 2.17a) (106 mg, 0.45 mmol) and2-bromo-1-(3-methoxyphenyl)ethanone (115 mg, 0.5 mmol). Gives 29 mg (17%yield) of a white powder. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=8 Hz,1H), 7.49 (s, 1H), 7.41 (t, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 5.86 (m,1H), 5.70 (dd, J=12 Hz, J=44 Hz, 1H), 5.34 (dd, J=8 Hz, J=16 Hz, 1H),5.24 (dd, J=4 Hz, J=16 Hz, 1H), 3.85 (s, 3H), 3.325 (d, J=4 Hz, 3H),2.88 (m, 1H), 1.98 (m, 2H), 1.76 (m, 2H), 1.52 (m, 1H), 1.49 (m, 1H),1.57 (d, J=8 Hz, 3H). MS 385 (MH⁺).

Example 2.19:5-(cyclohex-1-en-1-yl)-1-ethyl-5-methyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclohexenyl-1-ethyl-5-methylpyrimi-dine-2,4,6(1H,3H,5H)-trione(Example 2.19a) (75 mg, 0.3 mmol) and 2-bromoacetophenone (66 mg, 0.33mmol). Gives 23.2 mg (21% yield) of a white powder. ¹H NMR (400 MHz,CDCl₃) δ 7.98 (d, J=8 Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.50 (t, J=8 Hz,2H), 5.83 (m, 1H), 5.31 (q, J=16 Hz, J=24 Hz, 2H), 3.97 (m, 2H), 2.11(m, 2H), 1.97 (mm, 2H), 1.67 (s, 3H), 1.62 (m, 2H), 1.56 (m, 2H), 1.22(t, J=8 Hz, 3H). MS 369 (MH⁺).

Example 2.19a:5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17a using dimethyl2-cyclohexenyl-2-methylmalonate (Example 2.19b) (2 g, 8.85 mmol) andethyl urea (780 mg; 8.85 mmol). Gives 720 mg (33% yield) of a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (bs, 1H), 5.60 (m, 1H), 3.71(m, 2H), 1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 4H), 1.41 (s, 3H), 1.04(t, J=8 Hz, 3H). MS 251 (MH⁺).

Example 2.19b: Dimethyl 2-cyclohexenyl-2-methylmalonate

Prepared in a similar manner to Example 2.17b using dimethyl2-cyclohexenylmalonate (Example 2.19c) (5.7 g, 26.8 mmol) and methyliodide (1.67 mL, 26 mmol). Gives 4.28 g (71% yield) of a colorless oilwhich was used in to next step without future purification. ¹H NMR (400MHz, CDCl₃) δ 5.51 (m, 1H), 3.71 (s, 6H), 2.06 (m, 2H), 1.97 (m, 2H),1.83 (m, 1H), 1.70 (m, 1H), 1.59 (m, 3H), 1.54 (m, 1H), 1.53 (s, 3H). MS227 (MH⁺).

Example 2.19c: Dimethyl 2-cyclohexenylmalonate

To the mixture of dimethyl malonate (11.4 mL, 100 mmol), cyclohexanone(10.3 mL; 100 mmol) and acetic anhydride (11.3 mL, 120 mmol) was addedZnCl₂ (4.76 g, 35 mmol) activated with aniline (1.8 mL of aniline wasgradually added to ZnCl₂ and stirred at room temperature; resultingsolid was then added to the reaction mixture). Reaction mixture washeated at 100° C. for 70 h, then was diluted with water and extractedwith ether. Combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 120 g Silicycle column (Hexane/EtOAc 20%gradient, R_(f)=0.6) to obtain 5.78 g of desired product (13% yield). ¹HNMR (400 MHz, CDCl₃) δ 5.68 (m, 1H), 4.02 (s, 1H), 3.74 (s, 6H), 2.08(m, 4H), 1.85 (m, 2H), 1.59 (m, 2H). MS 213 (MH⁺).

Example 2.20:5-(cyclohex-1-en-1-yl)-1-ethyl-3-(2-(3-methoxyphenyl)-2-oxoethyl)-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.19a) (75 mg, 0.3 mmol) and2-bromo-1-(3-methoxy-phenyl)ethanone (76 mg, 0.33 mmol). Gives 59.5 mg(50% yield) of a white powder. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=8Hz, 1H), 7.49 (t, J=4 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.165 (dd, J=4 Hz,J=8 Hz, 1H), 5.83 (m, 1H), 5.291 (q, J=16 Hz, J=24 Hz, 2H), 3.97 (m,2H), 2.11 (m, 2H), 2.00 (mm, 2H), 1.67 (s, 3H), 1.62 (m, 2H), 1.56 (m,2H), 1.22 (t, J=8 Hz, 3H). MS 399 (MH⁺).

Example 2.21:5-(cyclohex-2-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

To the suspension of NaH (60%; 0.66 mmol; 26 mg) in 5 mL of anhydrousDMF was added solution of5-(cyclohex-2-enyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.17a) (71 mg; 0.3 mmol) in 1 mL of anhydrous DMF. The reactionmixture was stirred at ambient temperature for 15 minutes and then2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (1 eq; 0.5 mmol; 107 mg)was added to the reaction mixture and stirred at room temperature for 18h. The reaction was quenched with water (25 mL) and extracted with EtOAc(3×20 mL). The combined organic phases were washed with water (40 mL),brine (40 mL), and dried over MgSO₄ and solvents were evaporated. Crudeproduct was purified by preparative HPLC using a 40 minutes MeOH/H₂Ogradient of 5-95% to give after evaporation of solvents andlyophilization 31.2 mg of product (29% yield) as a white powder. ¹H NMR(400 MHz, CDCl₃) δ 9.21 (s, 1H), 8.85 (d, J=8 Hz, 1H), 8.26 (d, J=8 Hz,1H), 7.48 (dd, J=8 Hz, J=12 Hz, 1H), 5.86 (m, 1H), 5.70 (dd, J=12 Hz,J=44 Hz, 1H), 5.35 (dd, J=8 Hz, J=16 Hz, 1H), 5.26 (dd, J=4 Hz, J=16 Hz,1H), 3.325 (d, J=4 Hz, 3H), 2.88 (m, 1H), 1.98 (m, 2H), 1.76 (m, 2H),1.61 (m, 2H), 1.58 (d, J=8 Hz, 3H). MS 357 (MH⁺).

Example 2.22:5-(cyclohex-2-en-1-yl)-1-(2-(3-fluorophenyl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using of of5-(cyclohex-2-enyl)-1,5-dimethylpyrimi-dine-2,4,6(1H,3H,5H)-trione(Example 2.17a) (106 mg, 0.45 mmol) and2-bromo-1-(3-fluoro-phenyl)ethanone (109 mg, 0.5 mmol). Gives 35.5 mg(21% yield) of a white powder. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.505 (dd, J=8 Hz, J=20 Hz, 1H), 7.33 (t,J=8 Hz, 1H), 5.86 (m, 1H), 5.70 (dd, J=12 Hz, J=44 Hz, 1H), 5.32 (dd,J=8 Hz, J=16 Hz, 1H), 5.23 (dd, J=4 Hz, J=16 Hz, 1H), 3.32 (d, J=4 Hz,3H), 2.88 (m, 1H), 1.98 (m, 2H), 1.76 (m, 2H), 1.52 (m, 1H), 1.49 (m,1H), 1.57 (d, J=8 Hz, 3H). MS 385 (MH⁺).

Example 2.23:5-(cyclohex-1-en-1-yl)-1-ethyl-3-(2-(3-fluorophenyl)-2-oxoethyl)-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.19a) (75 mg, 0.3 mmol) and 2-bromo-1-(3-fluorophenyl)ethanone(72 mg, 0.33 mmol). Gives 20 mg (17% yield) of a white powder. ¹H NMR(400 MHz, CDCl₃) δ 7.76 (d, J=8 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.50 (m,1H), 7.33 (t, J=8 Hz, 1H), 5.83 (m, 1H), 5.291 (q, J=16 Hz, J=24 Hz,2H), 3.97 (m, 2H), 2.11 (m, 2H), 1.95 (mm, 2H), 1.66 (s, 3H), 1.62 (m,2H), 1.56 (m, 2H), 1.22 (t, J=8 Hz, 3H). MS 387 (MH⁺).

Example 2.24:5-(cyclohex-1-en-1-yl)-1-(2-(furan-2-yl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.15 using commerciallyavailable 5-cyclohexenyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(100 mg, 0.423 mmol), 2-bromo-1-(furan-2-yl)ethanone (123 mg, 0.651mmol), to obtain the desired product (77.9 mg, 53%). ¹H NMR (400 MHz,d₆-DMSO) δ 8.10 (dd, J=1.7, 0.7 Hz, 1H), 7.69 (dd, J=3.7, 0.6 Hz, 1H),6.80 (dd, J=3.7, 1.7 Hz, 1H), 5.79-5.74 (m, 1H), 5.14 (d, J=17.5 Hz,1H), 5.04 (d, J=17.5 Hz, 1H), 3.17 (s, 3H), 2.08-1.91 (m, 3H), 1.89-1.77(m, 1H), 1.62-1.42 (m, 4H), 1.53 (s, 3H). MS 345 (MH⁺).

Example 2.25:5-cyclopentyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclopentyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example2.25a) (67 mg, 0.3 mmol) and 2-bromoacetophenone (66 mg, 0.33 mmol).Gives 62 mg (60% yield) of a white powder. ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=8 Hz, 2H), 7.63 (t, J=8 Hz, 1H), 7.51 (t, J=8 v, 2H), 5.31(q, J=16 Hz, J=40 Hz, 2H), 3.32 (s, 3H), 2.45 (m, 1H), 1.77 (mm, 2H),1.63 (mm, 4H), 1.56 (m, 1H), 1.56 (s, 3H), 1.45 (m, 1H). MS 343 (MH⁺).

Example 2.25a:5-cyclopentyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17a using diethyl2-cyclopentyl-2-methylmalonate (Example 2.25b) (4.65 g, 19.2 mmol) andmethyl urea (1.42 g; 19.2 mmol). Gives 3 g (70% yield) of a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 5.60 (m, 1H), 3.05 (s, 3H),2.15 (m, 1H), 1.46 (m, 6H), 1.32 (s, 3H), 1.28 (m, 2H). MS 237 (MH⁺).

Example 2.25b: diethyl 2-cyclopentyl-2-methylmalonate

Prepared in a similar manner to Example 2.17b using diethyl2-methylmalonate (8.6 mL, 50 mmol) and bromocyclopentane (5.36 mL, 50mmol). Gives 9.36 g (77% yield) of a colorless oil which was used in tonext step without future purification. ¹H NMR (400 MHz, CDCl₃) δ 4.08(q, J=8 Hz, J=12, 2H), 2.42 (m, 1H), 1.62 (m, 2H), 1.46 (m, 4H), 1.27(m, 2H), 1.25 (s, 3H), 1.14 (t, J=8 Hz, 3H). MS 243 (MH⁺).

Example 2.26:5-cyclopentyl-1-(2-(3-fluorophenyl)-2-oxoethyl)-3,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclopentyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example2.25a) (67 mg, 0.3 mmol) and 2-bromo-1-(3-fluorophenyl)-ethanone (72 mg,0.33 mmol). Gave 27 mg (25% yield) of a white powder. ¹H NMR (400 MHz,CDCl₃) δ 7.76 (d, J=8 Hz, 1H), 7.665 (d, J=8 Hz, 1H), 7.505 (td, J=8 Hz,J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 5.27 (q, J=16 Hz, J=40 Hz, 2H), 3.32(s, 3H), 2.45 (m, 1H), 1.77 (mm, 2H), 1.63 (mm, 4H), 1.56 (m, 1H), 1.56(s, 3H), 1.45 (m, 1H). MS 361 (MH⁺).

Example 2.27:5-(cyclohex-1-en-1-yl)-1-ethyl-5-methyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.21 using5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.19a) (75 mg, 0.3 mmol) and 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (93 mg, 0.33 mmol). Gave 52.3 mg (47% yield) of a whitepowder. ¹H NMR (400 MHz, CDCl₃) δ 9.215 (d, J=4 Hz, 1H), 8.85 (dd, J=1.6Hz, J=4.8 Hz, 1H), 8.26 (dt, J=1.6 Hz, J=8.4 Hz, 1H), 7.475 (dd, J=4 Hz,J=8 Hz, 1H), 5.83 (m, 1H), 5.30 (q, J=16 Hz, J=24 Hz, 2H), 3.97 (m, 2H),2.11 (m, 2H), 1.97 (mm, 2H), 1.67 (s, 3H), 1.62 (m, 2H), 1.56 (m, 2H),1.22 (t, J=8 Hz, 3H). MS 370 (MH⁺).

Example 2.28:5-(cyclohex-1-en-1-yl)-5-methyl-1-(2-oxo-2-(pyridin-3-yl)ethyl)-3-propylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.21 using5-cyclohexenyl-5-methyl-1-propylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.28a) (79 mg, 0.3 mmol) and 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (93 mg, 0.33 mmol). Afforded 50 mg (44% yield) of a whitepowder. ¹H NMR (400 MHz, CDCl₃) δ 9.215 (d, J=4 Hz, 1H), 8.85 (dd, J=1.6Hz, J=4.8 Hz, 1H), 8.26 (dt, J=1.6 Hz, J=8.4 Hz, 1H), 7.475 (dd, J=4 Hz,J=8 Hz, 1H), 5.83 (m, 1H), 5.30 (q, J=16 Hz, J=24 Hz, 2H), 3.87 (m, 2H),2.11 (m, 2H), 1.97 (mm, 2H), 1.67 (s, 3H), 1.62 (m, 2H), 1.56 (m, 4H),0.94 (t, J=8 Hz, 3H). MS 384 (MH⁺).

Example 2.28a:5-cyclohexenyl-5-methyl-1-propylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17a using dimethyl2-cyclohexenyl-2-methylmalonate (Example 2.19b) (2 g, 8.85 mmol) andpropyl urea (903 mg; 8.85 mmol). Afforded 890 mg (38% yield) of a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (bs, 1H), 5.60 (m, 1H), 3.62(m, 2H), 1.98 (m, 2H), 1.93 (m, 1H), 1.79 (m, 2H), 1.51 (m, 5H), 1.42(s, 3H), 0.80 (t, J=8 Hz, 3H). MS N/A (MH⁺).

Example 2.29:5-cyclopentyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.21 using of5-cyclopentyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example2.25a) (67 mg, 0.3 mmol) and 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (93 mg, 0.33 mmol). Afforded 31.7 mg (31% yield) of a whitepowder. ¹H NMR (400 MHz, CDCl₃) δ 9.215 (d, J=4 Hz, 1H), 8.85 (dd, J=1.6Hz, J=4.8 Hz, 1H), 8.26 (dt, J=1.6 Hz, J=8.4 Hz, 1H), 7.475 (dd, J=4 Hz,J=8 Hz, 1H), 5.31 (q, J=16 Hz, J=40 Hz, 2H), 3.32 (s, 3H), 2.45 (m, 1H),1.77 (mm, 2H), 1.63 (mm, 4H), 1.56 (m, 1H), 1.56 (s, 3H), 1.45 (m, 1H).MS 344 (MH⁺).

Example 2.30:5-(cyclopent-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.30a) (67 mg, 0.3 mmol) and 2-bromoacetophenone (66 mg, 0.33mmol). Afforded 35.3 mg (35% yield) of a white powder. ¹H NMR (400 MHz,CDCl₃) δ 7.98 (d, J=8 Hz, 2H), 7.62 (t, J=8 Hz, 1H), 7.51 (t, J=8 Hz,2H), 5.75 (m, 1H), 5.31 (q, J=16 Hz, J=32 Hz, 2H), 3.34 (s, 3H), 2.38(m, 2H), 2.31 (m, 2H), 1.89 (m, 2H), 1.72 (s, 3H). MS 341 (MH⁺).

Example 2.30a:5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17a using dimethyl2-cyclopentenyl-2-methylmalonate (Example 2.30b) (626 mg, 2.95 mmol) andmethyl urea (218 mg; 2.95 mmol). Gave 208 mg (31% yield) of awhite-yellowish solid. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (bs, 1H), 5.66 (m,1H), 3.29 (s, 3H), 2.37 (m, 2H), 2.28 (m, 2H), 1.89 (m, 2H), 1.66 (s,3H). MS N/A (MH⁺).

Example 2.30b: dimethyl 2-cyclopentenyl-2-methylmalonate

Prepared in a similar manner to Example 2.17b using dimethyl2-cyclopentenylmalonate (30c) (5.53 g, 28 mmol) and methyl iodide (1.75mL, 28 mmol). Gave 626 mg (10% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 5.58(m, 1H), 3.64 (s, 6H), 2.29 (m, 4H), 1.81 (m, 2H), 1.48 (s, 3H). MS 213(MH⁺).

Example 2.30c: dimethyl 2-cyclopentenylmalonate

Prepared in a similar manner to Example 2.19c using dimethyl malonate(11.4 mL, 100 mmol) and cyclopentanone (8.85 mL, 100 mmol). Gave 5.53 g(28% yield) of a colorless oil, which was used in to the next stepwithout purification. MS 199 (MH⁺).

Example 2.31:5-(cyclopent-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.17 using5-cyclohexenyl-1-ethyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.30a) (67 mg, 0.3 mmol) and 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (93 mg, 0.33 mmol). Gave 35.4 mg (35% yield) of a whitepowder. ¹H NMR (400 MHz, CDCl₃) δ 9.215 (d, J=4 Hz, 1H), 8.85 (dd, J=1.6Hz, J=4.8 Hz, 1H), 8.26 (dt, J=1.6 Hz, J=8.4 Hz, 1H), 7.475 (dd, J=4 Hz,J=8 Hz, 1H), 5.75 (m, 1H), 5.31 (q, J=16 Hz, J=32 Hz, 2H), 3.34 (s, 3H),2.38 (m, 2H), 2.31 (m, 2H), 1.89 (m, 2H), 1.72 (s, 3H). MS 342 (MH⁺).

Example 2.32:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

5-cyclohexyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example2.32a) (453 μmol, 108 mg) and K₂CO₃ (680 μmol, 94 mg) were placed in avial, dissolved in dry DMF (2 mL) and stirred at room temperature for 2minutes. 2-Bromo-1-phenylethanone (498 μmol, 99 mg) was added andstirred at room temperature for 1 hour. 10% aqueous citric acid (10 mL)and water (10 mL) were added to precipitate the product. The product wascollected by filtration and washed with water, the in ACN andconcentrated to dryness. The compound was purified by silica gelchromatography (5→60% EtOAc/hexanes gradient) to give 156 mg (96%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.96 (m, 2H), 7.65-7.60 (m, 1H),7.54-7.48 (m, 2H), 5.36 (d, J=17.0 Hz, 1H), 5.27 (d, J=17.0 Hz, 1H),3.33 (s, 3H), 2.05-1.96 (m, 1H), 1.88-1.76 (m, 3H), 1.75-1.61 (m, 2H),1.54 (s, 3H), 1.33-1.18 (m, 3H), 1.18-1.05 (m, 2H). MS 357 (MH⁺)

Example 2.32a:5-cyclohexyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

The title compound was made from ethyl 2-cyano-2-cyclohexylpropanoate(2.0 mmol, 419 mg) (Example 2.4e) in a manner similar to Example 2.8aand Example 2.8b, to afford 217 mg (46% yield over 2 steps). ¹H NMR isconsistent with structure. MS N/A (MH⁺).

Example 2.33:1,5-dimethyl-5-(3-methylbut-2-en-1-yl)-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

The title compound was synthesized in a manner similar to Example 2.32from1,5-dimethyl-5-(3-methylbut-2-en-1-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.33a) (1.0 mmol, 224 mg), 2-bromo-1-phenylethanone (1.0 mmol,199 mg), and K₂CO₃ (1.1 mmol, 152 mg). Purified by silica gelchromatography (5→30% EtOAc/hexanes gradient). Gave 293 mg (86% yield).¹H NMR (400 MHz, CDCl₃) δ 8.01-7.96 (m, 2H), 7.66-7.60 (m, 1H),7.54-7.48 (m, 2H), 5.33 (d, J=17.1 Hz, 1H), 5.29 (d, J=17.0 Hz, 1H),5.07-5.01 (m, 1H), 3.31 (s, 3H), 2.72 (qd, J=13.7, 7.8 Hz, 2H), 1.71 (d,J=1.0 Hz, 3H), 1.61 (s, 3H), 1.60 (d, J=1.0 Hz, 3H). MS 343 (MH⁺)

Example 2.33a:1,5-dimethyl-5-(3-methylbut-2-en-1-yl)pyrimidine-2,4,6(1H,3H,5H)-trione

Placed 1-methylurea (3.0 mmol, 222 mg) and KOtBu (6.3 mmol, 707 mg) intoa vial flushed with nitrogen. Made up a solution of diethyl2-methyl-2-(3-methylbut-2-en-1-yl)malonate (Example 2.33b) (3.0 mmol,727 mg) in dry DMF (6 mL) and added this solution to the reaction vialwith stirring at room temperature. After 1 hour, quenched the reactionmixture with saturated aqueous NH₄Cl solution (1 mL) and 6N aqueous HCl(1 mL) and diluted with water (20 mL). Extracted with EtOAc (3×5 mL).Dried over NaCl, then MgSO₄, filtered, and concentrated to dryness.Purified by silica gel chromatography (1→10% MeOH/DCM gradient). Gave633 mg (94% yield). ¹H NMR is consistent with structure. MS N/A (MH⁺).

Example 2.33b: diethyl 2-methyl-2-(3-methylbut-2-en-1-yl)malonate

Placed NaH (60% dispersion in mineral oil, 10.0 mmol, 400 mg) into anitrogen-flushed vial with a stir bar and suspended in dry DMF (10 mL).Added diethyl 2-methylmalonate (10.0.0 mmol, 1705 μL) dropwise withstirring under nitrogen purge. When the reaction mixture had ceasedbubbling (5 minutes), added 1-bromo-3-methylbut-2-ene (10.0 mmol, 1164μL) via syringe and stirred at room temperature for 30 minutes. Quenchedwith saturated aqueous NH₄Cl (1 mL) and diluted with water (20 mL).Extracted with ether (1×15 mL, 2×10 mL), washed the ether extracts withwater (4×5 mL), dried over NaCl, then MgSO₄, filtered, and concentratedto dryness. Purified by silica gel chromatography (1→10% EtOAc/hexanesgradient). Gave 2117 mg (87% yield). ¹H NMR is consistent withstructure. MS N/A (MH⁺).

Example 2.34:1,5-dimethyl-5-(3-methylbut-2-en-1-yl)-3-(2-oxo-2-(pyridin-3-yl)ethyl)-pyrimidine-2,4,6(1H,3H,5H)-trione

The title compound was synthesized in a manner similar to Example 2.32from1,5-dimethyl-5-(3-methylbut-2-en-1-yl)pyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.33a) (1.0 mmol, 224 mg), 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (1.0 mmol, 281 mg), and K₂CO₃ (2.5 mmol, 346 mg). Purifiedby silica gel chromatography (40→100% EtOAc/hexanes gradient). Gave 118mg (34% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.22 (dd, J=2.3, 0.8 Hz, 1H),8.85 (dd, J=4.8, 1.7 Hz, 1H), 8.26 (ddd, J=8.0, 2.3, 1.8 Hz, 1H), 7.48(ddd, J=8.0, 4.8, 0.9 Hz, 1H), 5.33 (d, J=17.1 Hz, 1H), 5.28 (d, J=17.1Hz, 1H), 5.07-5.00 (m, 1H), 3.31 (s, 3H), 2.73 (qd, J=13.7, 7.8 Hz, 2H),1.71 (d, J=0.9 Hz, 3H), 1.61 (s, 3H), 1.60 (d, J=0.9 Hz, 3H). MS 344(MH⁺).

Example 2.35:5-benzyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In a 25 mL round-bottom flask,5-benzyl-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.35a) (20 mg, 0.049 mmol) was added to a solution of 6N HCl (2mL) and MeOH (2 mL). The reaction mixture was heated to 90° C. for 1 hr,then concentrated and purified by prep HPLC. The desired compound (5.2mg, 17%) was isolated as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.97-7.93 (m, 2H), 7.65-7.59 (m, 1H), 7.53-7.47 (m, 2H), 7.28-7.23 (m,4H), 7.08-7.03 (m, 1H), 5.22 (d, J=17.1 Hz, 1H), 5.04 (d, J=17.1 Hz,1H), 3.33 (d, J=13.0 Hz, 1H), 3.28 (d, J=13.0 Hz, 1H), 3.15 (s, 3H),1.75 (s, 3H). MS 365 (MH⁺).

Example 2.35a:5-benzyl-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (3.0 mL),5-benzyl-1-methyl-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.35b) (30 mg, 76 umol), and the solution was cooled to 0° C.in an ice bath. NaH (6 mg, 152 umol), and iodomethane (10 uL, 152 umol)were added, the ice bath was removed and the reaction medium was stirredvigorously at room temperature for 2 hr, then diluted with water andextracted with EtOAc (3×10 mL). The combined organic phases were washedwith brine and dried over MgSO₄, and the solvent was evaporated. Theresidue was purified by mass-triggered HPLC to obtain the pure desiredproduct (20 mg, 64%) as a light yellow solid. MS 409 (MH⁺). H¹-NMR isconsistent with the structure.

Example 2.35b:5-benzyl-1-methyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous EtOH (5.0 mL) and sodium metal (2.5 mmol, 58 mg). Afterstirring for 40 min, 1-methyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)urea(Example 2.35c) (236 mg, 1 mmol) was added followed by diethyl2-benzylmalonate (250 mg, 1 mmol). The reaction mixture was refluxed at100° C. for 18 hrs then quenched by H₂O (1 mL). The reaction mixture wasconcentrated, diluted with H₂O (2 mL) and acidified with 1N HCl to pH˜2.The aqueous layer was extracted with DCM (3×10 mL) and the organic layerwas dried over MgSO₄, concentrated and purified by preparative HPLC toobtain the pure product (80 mg, 20%) as a clear colorless oil. MS 395(MH⁺). H¹-NMR was consistent with the structure.

Example 2.35c: 1-methyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)urea

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous THF (15.0 mL), 4-nitrophenyl methylcarbamate (35 g) (1.0 g,5.09 mmol), triethylamine (850 uL, 6.1 mmol) and(2-phenyl-1,3-dioxolan-2-yl)methanamine (Example 2.35d) (1.2 g, 6.1mmol). The resulting reaction mixture was stirred at room temperaturefor 18 hrs and concentrated. The residue was treated with H₂O andextracted with 20% ACN in DCM (3×20 mL). The organic layer was washedwith 2N NaOH, brine, dried over MgSO₄ and concentrated. The desiredproduct (1.1 g, 91%) was obtained as a white solid. MS 237 (MH⁺). H¹-NMRwas consistent with the structure.

Example 2.35d: (2-phenyl-1,3-dioxolan-2-yl)methanamine

In an oven-dried, 500 mL round-bottom flask, were added EtOH (300 mL),2-((2-phenyl-1,3-dioxolan-2-yl)methyl)isoindoline-1,3-dione (Example2.35e) (18 g, 58 mmol) and hydrazine (19 mL, 580 mmol). The resultingmixture was heated up to 80° C. for 1.5 hrs. The clear solution turnedcloudy and a precipitate formed. After removal of most of the EtOH, a30% aqueous NaOH solution was added until all solids were dissolved. Theaqueous layer was extracted with Et₂O (3×25 mL) and the combined organiclayers were dried over MgSO₄ and concentrated to give desired product(10.0 g, 97%) as a light yellow solid. MS 180 (MH⁺). H¹-NMR isconsistent with the structure.

Example 2.35e:2-((2-phenyl-1,3-dioxolan-2-yl)methyl)isoindoline-1,3-dione

In an oven-dried, 500 mL round-bottom flask, were added benzene (250mL), 2-(2-oxo-2-phenylethyl)isoindoline-1,3-dione (Example 2.35f) (24 g,90 mmol) and ethylene glycol (46.5 mL, 900 mmol) followed byp-toluenesulfonic acid (800 mg, 4.65 mmol). The resulting mixture washeated to 110° C. for 20 hrs (with Dean Stark apparatus). The reactionmixture was cooled to room temperature and benzene was removed in vacuo.The reaction mixture was quenched with H₂O and extracted with Et₂O(3×200 mL). The combined organic layers were dried over MgSO₄ andconcentrated to give the desired product (23 g, 97%) as a white solid.MS 310 (MH⁺). H¹-NMR is consistent with the structure.

Example 2.35f: 2-(2-oxo-2-phenylethyl)isoindoline-1,3-dione

In an oven-dried, 500 mL round-bottom flask, were added DMF (80 mL),2-bromo-1-phenylethanone (20 g, 100 mmol) and potassium phthalimide(18.5 g, 100 mmol) was added to the suspension in three portions. Theresulting mixture was stirring at r.t for 20 hrs (with Dean Starkapparatus), cooled to room temperature and the DMF was removed in vacuo.The reaction residue was diluted with H₂O and extracted with DCM (3×100mL). The combined organic layers were dried over MgSO₄ and concentratedto give a light yellow solid. The solid was titrated with Et₂O to givethe pure product (24 g, 90%) as a white solid. MS 266 (MH⁺). H¹-NMR isconsistent with the structure.

Example 2.35g: 4-nitrophenyl methylcarbamate

In an oven-dried, N₂-flushed, 1.0 L round-bottom flask, were addedanhydrous DCM (722.0 mL), 4-nitrophenylchloroformate (6.0 g, 29.8 mmol),anhydrous Na₂CO₃ (7.3 g, 68.9 mmol), and methylamine hydrochloride (2.1g, 30.7 mmol). The reaction medium was stirred vigorously at roomtemperature and under N₂ for 8 days. The resulting heterogeneousreaction medium was filtered and the filtrate was evaporated. Theobtained residue was recrystallised from EtOH to obtain the desiredproduct as white needles (3.95 g, 68%). ¹H NMR (400 MHz, d₆-DMSO) δ8.28-8.22 (m, 2H), 7.96-7.86 (m, 1H), 7.43-7.35 (m, 2H), 2.75-2.65 (m,3H). MS no ionization.

Example 2.36:5-allyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Anhydrous DMF (3.0 mL) and5-allyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example 2.36a)(74 mg, 0.37 mmol) were added to an oven-dried, N₂-flushed, smallround-bottom flask and the solution was cooled to 0° C. in an ice bath.NaH (18 mg, 0.45 mmol), and 2-bromo-1-phenylethanone (90 mg, 0.45 mmol)were added, the ice bath was removed and the reaction was stirredvigorously at room temperature for 2 hr. The reaction was quenched withwater (10 mL) and extracted with DCM (3×10 mL). The combined organicphases were washed with brine and dried over MgSO₄, and solvents wereevaporated. The residue was purified by preparative HPLC affording thedesired product as a clear colorless oil (35 mg, 30%). ¹H NMR (400 MHz,CDCl₃) δ 8.01-7.96 (m, 2H), 7.67-7.61 (m, 1H), 7.54-7.48 (m, 2H),5.81-5.69 (m, 1H), 5.32 (s, 2H), 5.18-5.11 (m, 2H), 3.31 (s, 3H),2.78-2.73 (m, 2H), 1.63 (s, 3H). MS 315 (MH⁺).

Example 2.36a: 5-allyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Anhydrous DMF (10.0 mL) and 1-methylurea (74 mg, 1 mmol) were added toan oven-dried, N₂-flushed, small round-bottom flask and the solution wascooled to 0° C. in an ice bath. NaH (18 mg, 0.45 mmol) was added withstirring for 10 min, then diethyl 2-allyl-2-methylmalonate (Example2.36b) (230 mg, 1 mmol) was added. The ice bath was removed and thereaction mixture was stirred vigorously at room temperature for 2 hr,then quenched with H₂O. The aqueous layer was acidified by 1N HCl andextracted with DCM (3×10 mL). The combined organic phase was washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography using a 12 g Silicycle column andMeOH/DCM as eluant to obtain the pure product (170 mg, 93%) as a clearoil. MS 197 (M+H⁺). H¹-NMR is consistent with the structure.

Example 2.36b: Diethyl 2-allyl-2-methylmalonate

Diethyl 2-allyl-2-methylmalonate was made from diethyl 2-methylmalonate(10.0 mmol, 1705 μL) and allyl bromide (10.0 mmol, 846 μL) in a mannersimilar to Example 2.37b below to afford 1798 mg (84% yield) of the pureproduct. ¹H NMR was consistent with structure.

Example 2.37:(E)-5-(but-2-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Anhydrous DMF (3.0 mL) and(E)-5-(but-2-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.37a) (20 mg, 0.1 mmol), were added to an oven-dried, N₂—flushed, small round-bottom flask and the solution was cooled to 0° C.in an ice bath. NaH (6 mg, 0.12 mmol), and 2-bromo-1-phenylethanone (24mg, 0.12 mmol). were added and the ice bath was removed. The reactionmixture was stirred vigorously at room temperature for 2 hr, thenquenched with H₂O (5 mL). The aqueous layer was extracted with DCM (3×10mL). The combined organic phase was washed with brine, dried over MgSO₄,and concentrated in vacuo. The residue was purified by by mass-triggeredHPLC to obtain the pure desired product (10 mg, 30%) as a clear oil. ¹HNMR (400 MHz, CDCl₃) δ 8.02-7.95 (m, 2H), 7.66-7.60 (m, 1H), 7.54-7.48(m, 2H), 5.62-5.51 (m, 1H), 5.40-5.33 (m, 1H), 5.31 (d, J=1.2 Hz, 2H),3.31 (s, 3H), 2.70 (d, J=13.5 Hz, 1H), 2.65 (d, J=13.5 Hz, 1H),1.68-1.63 (m, 3H), 1.59 (s, 3H). MS 329 (MH⁺).

Example 2.37a:(E)-5-(but-2-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Anhydrous DMF (8.0 mL) and 1-methylurea (111 mg, 1.5 mmol) were added toan oven-dried, N₂-flushed, small round-bottom flask and the solution wascooled to 0° C. in an ice bath. NaH (18 mg, 0.45 mmol) was added withstirring for 10 min, then (E)-diethyl 2-(but-2-en-1-yl)-2-methylmalonate(Example 2.37b) (342 mg, 1.5 mmol) was added. The ice bath was removedand the reaction mixture was stirred vigorously at room temperature for18 hr, then quenched with H₂O. The aqueous layer was acidified by 1N HCland extracted with DCM (3×10 mL). The combined organic phase was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by preparative HPLC to obtain the pure product (150 mg, 30%) asa clear colorless oil. MS 211 (MH⁺). H¹-NMR is consistent with thestructure.

Example 2.37b: (E)-diethyl 2-(but-2-en-1-yl)-2-methylmalonate

KOtBu (10.0 mmol, 1122 mg) was placed in a 40 mL vial flushed withnitrogen and dry DMF (10 mL) was added with stirring at room temperaturefor 5 minutes. Diethyl 2-methylmalonate was added via syringe andstirred at room temperature an additional 5 minutes. The reactionmixture was placed in an ice-bath and cooled to 0° C. then(E)-1-bromobut-2-ene was added via syringe and stirred at 0° C., warmingslowly to room temperature overnight. The reaction was quenched withsat. aqueous NH₄Cl (1 mL) and water (15 mL) was added. The aqueoussolution was extracted with hexanes (3×10 mL), washed with brine, thendried over MgSO₄, filtered, and concentrated in vacuo to afford 2008 mgof product (88% yield). ¹H NMR is consistent with structure.

Example 2.38:5-benzyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (15.0 mL),5-benzyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Example 2.38a)(480 mg, 1.95 mmol), and the solution was cooled to 0° C. in an icebath. NaH (86 mg, 2.1 mmol), and 2-bromo-1-(pyridin-3-yl)ethanonehydrobromide (548 mg, 1.95 mmol) were added and the ice bath wasremoved. The reaction mixture was stirred vigorously at room temperaturefor 2 hr, diluted with water (15 mL) and extracted with DCM (3×20 mL).The combined organic phase was washed with brine and dried over MgSO₄,and solvents were evaporated. The residue was purified by mass-triggeredHPLC to give the pure product (300 mg, 42%) as a clear colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 9.177 (m, 1H), 8.837 (m, 1H), 8.211 (m, 1H),7.451 (m, 1H), 7.260 (m, 3H), 7.039 (m, 3H), 5.178 (d, J=16.8 Hz, 1H),5.014 (d, J=16.8 Hz, 1H), 3.319 (d, J=12.8 Hz, 1H), 3.265 (d, J=12.8 Hz,1H), 3.160 (s, 3H), 1.753 (s, 3H). MS 366 (MH⁺).

Example 2.38a: 5-benzyl-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (10.0 mL), 1-methylurea (280 mg, 3.78 mmol), and thesolution was cooled to 0° C. in an ice bath. NaH (332 mg, 8.31 mmol) wasadded with stirring for 10 min, then diethyl 2-benzyl-2-methylmalonate(Example 2.38b) (1.0 g, 3.78 mmol) was added. The reaction mixture wasallowed to warm to room temperature with stirring for 18 hr and thenquenched by H₂O. The aqueous layer was acidified by 1N HCl and extractedwith DCM (3×15 mL). The combined organic phase was washed with brine,dried over MgSO₄, and solvents were evaporated. The residue was purifiedby flash chromatography using a 12 g Silicycle column and MeOH/DCM aseluant to obtain the pure product (900 mg, 96%) as a clear colorlessoil. MS 247 (MH⁺). H¹-NMR is consistent with the structure.

Example 2.38b: diethyl 2-benzyl-2-methylmalonate

Anhydrous DMF (20.0 mL) and diethyl 2-benzylmalonate (1.5 g, 6 mmol)were placed in an oven-dried, N₂-flushed, 100 mL round-bottom flask andcooled to 0° C. in an ice bath. NaH (263 mg, 6.5 mmol), and iodomethane(548 ul, 6 mmol) were added and the reaction mixture was allowed to warmto room temperature. The reaction medium was stirred vigorously at roomtemperature for 2 hr, quenched with water (20 mL) and extracted with DCM(3×25 mL). The combined organic phase was washed with brine, dried overMgSO₄, and solvents were evaporated. The residue was purified by flashchromatography using a 12 g Silicycle column and EtOAc/Hexanes as eluantto obtain the pure product (1.1 g, 69%) as a clear colorless oil. MS 265(MH⁺). H¹-NMR is consistent with the structure.

Example 2.39:5-(3-fluorobenzyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL) and5-(3-fluorobenzyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.39a) (315 mg, 1.2 mmol) and the solution was cooled to 0° C.in an ice bath. NaH (53 mg, 1.32 mmol), and 2-bromo-1-phenylethanone(262 mg, 1.32 mmol) were added and the ice bath was removed. Thereaction medium was stirred vigorously at room temperature for 2 hr,quenched with water (10 mL) and extracted with DCM (3×10 mL). Thecombined organic phase was washed with brine and dried over MgSO₄, andsolvents were evaporated. The residue was purified by prep HPLC to givethe pure product (302 mg, 65%) as a clear colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.94 (m, 2H), 7.61 (m, 1H), 7.49 (m, 2H), 7.201 (m, 1H),6.95 (m, 1H), 6.7-96.87 (m, 2H), 5.22 (d, J=16.8 Hz, 1H), 5.09 (d,J=16.8 Hz, 1H), 3.32 (d, J=13.2 Hz, 1H), 3.19 (d, J=13.2 Hz, 1H), 3.19(s, 3H), 1.75 (s, 3H). MS 383 (MH⁺).

Example 2.39a:5-(3-fluorobenzyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Anhydrous DMF (8.0 mL) and 1-methylurea (160 mg, 2.1 mmol) were placedin an oven-dried, N₂-flushed, small round-bottom flask and cooled to 0°C. in an ice bath. NaH (157 mg, 3.92 mmol) was added and stirred for 10min, then dimethyl 2-(3-fluorobenzyl)-2-methylmalonate (Example 2.39b)(1.0 g, 3.78 mmol) was added. The reaction medium was stirred vigorouslyat room temperature for 18 hr, then quenched by H₂O (10 mL). The aqueouslayer was acidified by 1N HCl, and extracted with DCM (3×10 mL). Thecombined organic phases were washed with brine and dried over MgSO₄, andsolvents were evaporated. The residue was purified by flashchromatography using a 12 g Silicycle column and MeOH/DCM as eluant toobtain the pure product (400 mg, 40%) as a clear oil. MS 265 (MH⁺).H¹-NMR is consistent with the structure.

Example 2.39b: dimethyl 2-(3-fluorobenzyl)-2-methylmalonate

Anhydrous DMF (10.0 mL) and dimethyl 2-methylmalonate (1.0 g, 6.8 mmol),were placed in an oven-dried, N₂-flushed, small round-bottom flask andcooled to 0° C. in an ice bath. NaH (272 mg, 6.8 mmol) was added then1-(bromomethyl)-3-fluorobenzene (823 ul, 6.8 mmol). The reaction mediumwas stirred vigorously at room temperature for 24 hr, then quenched byH₂O (10 mL) and extracted with DCM (3×10 mL). The combined organicphases were washed with brine and dried over MgSO₄, and solvents wereevaporated. The residue was purified by flash chromatography using a 12g Silicycle column and EtOAc/Hex as eluant to obtain the pure product(1.6 g, 93%) as a clear oil. MS 255 (MH⁺). H¹-NMR is consistent with thestructure.

Example 2.40:5-(4-fluorobenzyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.39 starting with5-(4-fluorobenzyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.40a) (157 mg, 0.6 mmol), and 2-bromo-1-phenylethanone (142mg, 0.7 mmol) to obtain the desired product (165 mg, 72%) as a clearcolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (m, 2H), 7.61 (m, 1H),7.49 (m, 2H), 7.04 (m, 2H), 6.93 (m, 2H), 5.20 (d, J=17.2 Hz, 1H), 5.09(d, J=17.2 Hz, 1H), 3.26 (d, J=13.6 Hz, 1H), 3.30 (d, J=13.6 Hz, 1H),3.18 (s, 3H), 1.74 (s, 3H). MS 383 (MH⁺). MS 383 (MH⁺).

Example 2.40a:5-(4-fluorobenzyl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Prepared in a similar manner to Example 2.39a starting with dimethyl2-(4-fluorobenzyl)-2-methylmalonate (Example 2.40b) (500 mg, 1.96 mmol)to obtain the pure product (385 mg, 74%) as a clear oil. MS 265 (MH⁺).H¹-NMR is consistent with the structure.

Example 2.40b: dimethyl 2-(4-fluorobenzyl)-2-methylmalonate

Prepared in a similar manner to Example 2.39b starting with dimethyl2-(4-fluorobenzyl)malonate (1.0 g, 4.1 mmol) to obtain the pure product(800 mg, 77%) as a clear oil. MS 255 (MH⁺). H¹-NMR is consistent withthe structure.

Example 2.41:2-(5-(5-(cyclohex-1-en-1-yl)-3,5-dimethyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)-N-phenylacetamide

5-(Cyclohex-1-en-1-yl)-1,5-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione(Example 2.8a) (500 μmol, 118 mg) was placed in a vial with dry DMF (5mL). K₂CO₃ (750 μmol, 104 mg), was added and the reaction was stirredfor 1 minute at room temperature. 2-chloro-N-phenylacetamide (550 μmol,93 mg) was added and stirred at room temperature for 2 hours, thendiluted with water (30 mL) and stirred to precipitate the product. Theprecipitate was collected by filtration, washed with water, anddissolved in DCM (10 mL). The solution was dried with NaCl, then MgSO₄,filtered, and concentrated in vacuo. Purification by silica gelchromatography (10→60% EtOAc/hexanes gradient) gave 166 mg (90% yield).¹H NMR (400 MHz, d₆-DMSO) δ 10.22 (s, 1H), 7.55-7.49 (m, 2H), 7.33-7.26(m, 2H), 7.07-7.01 (m, 1H), 5.79-5.74 (m, 1H), 4.62 (d, J=16.2 Hz, 1H),4.48 (d, J=16.2 Hz, 1H), 3.16 (s, 3H), 2.06-1.89 (m, 3H), 1.86-1.75 (m,1H), 1.51 (s, 3H), 1.60-1.38 (m, 4H). MS 370 (MH⁺).

Example 2.42:5-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.42a) (0.89 g, 2.70 mmol), Cs₂CO₃ (1.30 g, 4.0 mmol), 3 mLanhydrous DMF and methyl iodide (0.460 g, 3.2 mmol). The reactionmixture was stirred vigorously at ambient temperature for 24 hours whereit was diluted with 50 mL ethyl acetate and washed with water (2×50 mL),brine (1×50 mL) and dried with Na₂SO₄. The solvent was evaporated andthe residue purified by column chromatography utilizing an 80 gSilicycle column and elution with 0-40% ethyl acetate/hexanes to afforda mixture of diastereomers. The diastereomers were separated by HPLCutilizing a 40 minute method to afford the title compound (0.147 g) as asemi-solid. The residue was concentrated from EtOH 3× and dried on thelyophilizer for 48 h to afford the title compound as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ 8.05-8.03 (m, 2H), 7.74-7.70 (m, 1H),7.59-7.56 (m, 2H), 4.97 (s, 2H), 2.81 (s, 3H), 2.39-2.37 (m, 1H),2.18-2.16 (m, 1H), 1.85-1.80 (m, 1H), 1.50-1.47 (m, 2H), 1.44 (s, 3H),1.38-1.32 (m, 1H), 1.27-1.13 (m, 4H), 1.02-0.99 (m, 1H); MS 341 (MH⁺).

Example 2.42a:5-bicyclo[2.2.1]heptan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-5-methylimidazolidine-2,4-dione (Example2.42b) (1.7 g, 8.31 mmol), 10 mL DMF, K₂CO₃ (1.72 g, 12.5 mmol) andbromoacetophenone (1.65 g, 8.31 mmol). The flask was sealed and thereaction mixture was stirred at ambient temperature for 18 hrs. Thereaction was quenched with water (25 mL) and extracted with EtOAc (3×20mL). The organic layers were combined, washed with water (40 mL), brine(40 mL), and dried over Na₂SO₄. Solvent was evaporated, and theresulting residue was purified by column chromatography utilizing aSilicycle column (40 g) and elution with 10%-40% ethyl acetate/hexanes.The title compound was isolated 1.9 g (71%) as a mixture ofdiastereomers. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.4 (s, 1H), 8.37 (s, 1H),8.07-8.02 (m, 4H), 7.74-7.69 (m, 2H), 7.60-7.55 (m, 4H), 4.94 (s, 2H),4.91 (s, 2H), 2.28-2.26 (m, 1H), 2.21-2.18 (m, 2H), 2.12-2.10 (m, 1H),1.77-1.70 (m, 2H), 1.50-1.34 (m, 12H), 1.27-1.21 (m, 5H), 1.13-0.99 (m,5H); MS 327 (MH⁺).

Example 2.42b:5-bicyclo[2.2.1]heptan-2-yl)-5-methylimidazolidine-2,4-dione

To a 150 mL pressure tube, were added H₂O (30 mL), commerciallyavailable 1-bicyclo[2.2.1]hept-2-ylethanone (5.3 g, 38.4 mmol) in MeOH(50 mL), (NH₄)₂CO₃ (11.4 g, 119.1 mmol), and KCN (2.75 g, 42.3 mmol) inH₂O (10 mL) drop-wise over 5 minutes. The tube was sealed and heated at55° C. for 24 hours. The reaction medium was allowed to cool to roomtemperature. 20 mL H₂O was added and the reaction was cooled to 0° C.for two hours. The white precipitate was filtered and washed with coldH₂O and dried to obtain the title compound 8.0 g (quantitative) as awhite crystalline solid consisting of two diastereomers. ¹H NMR (400MHz, DMSO-d₆) δ 10.5 (br s, 2H), 7.92-7.87 (m, 2H), 2.17-2.15 (m, 3H),1.77-1.76 (m, 1H), 1.67-1.59 (m, 2H), 1.47-1.34 (m, 8H), 1.25 (s, 3H),1.21-1.18 (m, 2H), 1.13-1.05 (m, 7H), 1.01-0.96 (m, 2H); MS 209 (MH⁺).

Example 2.43:5-cyclohexyl-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (6.0 mL), 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.47a) (199.9 mg, 951 umol), NaH (40.0 mg, 1000 umol), andafter about 10 minutes vigorous stirring2-bromo-1-(3-hydroxyphenyl)ethanone (225.0 mg, 1047 umol). The reactionmedium was stirred vigorously overnight, diluted with water andextracted with excess EtOAc (3×). The combined organic phases werewashed with brine and dried over MgSO₄, and solvents were evaporated.The residue was diluted in a minimum amount of MeOH was purified bypreparative HPLC using a 40 minutes CH₃CN/H₂O gradient as eluant toobtain the pure desired product (148.0 mg, 45%). ¹H NMR (400 MHz,d₆-DMSO) δ 9.91 (s, 1H), 7.53-7.46 (m, 1H), 7.37 (t, J=7.9 Hz, 1H),7.33-7.31 (m, 1H), 7.11-7.07 (m, 1H), 4.87 (d, J=0.9 Hz, 2H), 2.81 (s,3H), 1.79-1.66 (m, 4H), 1.66-1.56 (m, 2H), 1.38 (s, 3H), 1.37-1.28 (m,1H), 1.26-1.11 (m, 2H), 1.11-0.86 (m, 2H). MS 345 (MH⁺).

Example 2.44:5-cyclopentyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (3.3 mL),5-cyclopentyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.44a) (102.7 mg, 342 umol), K₂CO₃ (58.0 mg, 420 umol), and MeI(100 uL, 1606 umol). The reaction medium was stirred vigorously at roomtemperature for 21 hours, diluted with water and extracted with EtOAc(3×). The combined organic phases were washed with brine and dried overMgSO₄, and solvents were evaporated. The residue was purified bypreparative HPLC using a CH₃CN/H₂O gradient as eluant to obtain the puredesired product (38 mg, 36%) as an oily film. ¹H NMR (400 MHz, DMSO-d₆)δ 8.05-8.03 (m, 2H), 7.73-7.69 (m, 1H), 7.59-7.56 (m, 2H), 4.97 (s, 2H),2.84 (s, 3H), 2.35-2.31 (m, 1H), 1.85-1.73 (m, 1H), 1.68-1.46 (m, 6H),1.42 (s, 3H), 1.34-1.24 (m, 1H). MS 315 (MH⁺).

Example 2.44a:5-cyclopentyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (20.0 mL), 5-cyclopentyl-5-methylimidazolidine-2,4-dione(Example 2.44b) (1.0 g, 5.5 mmol), K₂CO₃ (925 mg, 6.7 mmol), and2-bromo-1-phenylethanone (1.15 g, 5.8 mmol). The reaction medium wasstirred vigorously at room temperature for 19 hours, diluted with waterand extracted with EtOAc (3×25 mL). The combined organic phases werewashed with brine and dried over MgSO₄, and solvents were evaporated.The residue was purified by flash chromatography using a 120 g Silicyclecolumn and a Hexanes/EtOAc gradient as eluant to obtain the pure desiredproduct (1.1 g, 67%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41(s, 1H), 8.04-8.02 (m, 2H), 7.71-7.68 (m, 1H), 7.58-7.54 (m, 2H), 4.90(s, 2H), 2.22-2.14 (m, 1H), 1.76-1.72 (m, 1H), 1.62-1.45 (m, 5H),1.43-1.28 (m, 2H), 1.35 (s, 3H). MS 301 (MH⁺).

Example 2.44b: 5-cyclopentyl-5-methylimidazolidine-2,4-dione

In a N₂-flushed 150 mL pressure tube, were added H₂O (32 mL),1-cyclopentylethanone (3.0 g, 26.7 mmol) in MeOH (40 mL), (NH₄)₂CO₃ (8g, 82.9 mmol), and KCN (1.44 g, 29.4 mmol) in H₂O (10 mL) was addeddropwise over a few minutes. The tube was sealed and heated at 50° C.for 50 hours. The reaction medium was allowed to cool down and theobtained white precipitate was filtered and washed with a little coldH₂O and dried to obtain a first crop of the desired pure product (2.81g, 58%). Further precipitate formed in the mother liquors and wasfiltered and washed as above to obtain a second crop of pure desiredcompound (716 mg, 14.7%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H),7.96 (s, 1H), 2.11-2.02 (m, 1H), 1.72-1.66 (m, 1H), 1.56-1.41 (m, 5H),1.33-1.24 (m, 1H), 1.24 (s, 3H), 1.16-1.08 (m, 1H). MS 183 (MH⁺).

Example 2.45:5-cyclopentyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (3.0 mL),5-cyclopentyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.45a) (65.7mg, 335 umol), and at 0° C. NaH (38.0 mg, 950 umol), and2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (119 mg, 424 umol). Thereaction medium was stirred vigorously at room temperature overnight,diluted with water and extracted with EtOAc (3×10 mL). Combined organicphases were washed with brine and dried over MgSO₄, and solvents wereevaporated. The residue was purified by flash chromatography using a 12g Silicycle column and a DCM/EtOAc gradient as eluant to obtain the pureproduct (63.8 mg, 60%) as an oily film. ¹H NMR (400 MHz, CDCl₃) δ 9.21(s, br, 1H), 8.85 (s, br, 1H), 8.32 (s, br, 1H), 7.54 (s, br, 1H), 4.92(s, 2H), 2.94 (s, 3H), 2.32-2.25 (m, 1H), 1.93-1.55 (m, 7H), 1.52 (s,3H), 1.44-1.34 (m, 1H). MS 316 (MH⁺).

Example 2.45a: 5-cyclopentyl-1,5-dimethylimidazolidine-2,4-dione

In a N₂-flushed round-bottom flask, were added anhydrous CH₃CN (7.7 mL),5-cyclopentyl-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.45b) (243.4 mg, 769 umol), and at 0° C. an ice-cooledsolution of ammonium cerium IV nitrate (886.0 mg, 1616 umol) in H₂O (4.6mL) was added dropwise. The reaction medium was monitored by TLC,stirred vigorously at room temperature overnight, diluted with brine andextracted with EtOAc (3×15 mL). The combined organic phases were washedagain with brine and dried over MgSO₄, and solvents were evaporated. Theresidue was purified by flash chromatography using a 40 g Silicyclecolumn and a Hexanes/EtOAc gradient as eluant to obtain the pure desiredproduct (72.1 mg, 48%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 2.72(s, 3H), 2.26-2.18 (m, 1H), 1.74-1.66 (m, 1H), 1.63-1.45 (m, 6H), 1.31(s, 3H), 1.09-1.01 (m, 1H). MS 197 (MH⁺).

Example 2.45b:5-cyclopentyl-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (4.0 mL),5-cyclopentyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.45c) (287.5 mg, 951 umol), and NaH (49.0 mg, 1225 umol), andMeI (100 uL, 1606 umol). The reaction medium was stirred vigorously atroom temperature overnight, then diluted with water and extracted withEtOAc (3×10 mL). The combined organic phases were washed with brine anddried over MgSO₄, and solvents were evaporated. The residue was purifiedby flash chromatography using a 40 g Silicycle column and aHexanes/EtOAc gradient as eluant to obtain the pure desired product(253.6 mg, 84%). ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J=8.0, 2H), 6.82 (d,J=8.4, 2H), 4.58 (s, 2H), 3.78 (s, 3H), 2.86 (s, 3H), 2.25-2.16 (m, 1H),1.79-1.72 (m, 1H), 1.65-1.43 (m, 6H), 1.37 (s, 3H), 1.01-0.92 (m, 1H).MS 317 (MH⁺).

Example 2.45c:5-cyclopentyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (4.0 mL), 5-cyclopentyl-5-methylimidazolidine-2,4-dione(Example 2.44b) (200 mg, 1.10 mmol), K₂CO₃ (232 mg, 1.68 mmol), KI (18mg, 0.11 mmol) and 1-(bromomethyl)-4-methoxybenzene (240 uL, 1.67 mmol).The reaction medium was stirred vigorously at room temperatureovernight, diluted with water and extracted with EtOAc (3×10 mL). Thecombined organic phases were washed with brine and dried over MgSO₄, andsolvents were evaporated. The residue was purified by flashchromatography using a 40 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure desired product (287.5 mg, 87%).¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J=8.4, 2H), 6.83 (d, J=8.4, 2H), 4.57(s, 2H), 3.79 (s, 3H), 2.28-2.19 (m, 1H), 1.85-1.78 (m, 1H), 1.64-1.40(m, 6H), 1.40 (s, 3H), 1.13-1.04 (m, 1H). MS 303 (MH⁺).

Example 2.46:1,5-dimethyl-5-(2-methylbenzyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from1,5-dimethyl-5-(2-methylbenzyl)imidazolidine-2,4-dione (Example 2.46a)(0.075 g, 0.33 mmol), and 2-bromo-1-phenylethanone (0.063 g, 0.33 mmol),to obtain the pure desired product as a white solid (80 mg, 70%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.01-7.99 (m, 2H), 7.71-7.67 (m, 1H), 7.14-7.08 (m,3H), 7.03-7.00 (m, 1H), 4.78 (s, 2H), 3.14 (d, J=14.6 Hz, 1H), 3.05 (d,J=14.6 Hz, 1H), 2.90 (s, 3H), 2.28 (s, 3H) 1.54 (s, 3H); MS 351 (MH⁺).

Example 2.46a: 1,5-dimethyl-5-(2-methylbenzyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from3-(4-methoxybenzyl)-1,5-dimethyl-5-(2-methylbenzyl)imidazolidine-2,4-dione(Example 2.0.46b) (0.47 g, 1.33 mmol) in 5 mL CH₃CN and CAN (1.9 g, 3.46mmol) in 1 mL H₂O, to obtain the pure desired product as a beige solid(256 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.5 (s, 1H), 7.13-7.05 (m,3H), 6.93-6.91 (m, 1H), 3.01 (d, J=14.5 Hz, 1H), 2.93 (d, J=14.5 Hz,1H), 2.83 (s, 3H), 2.28 (s, 3H), 1.42 (s, 3H); MS 233 (MH⁺).

Example 2.46b:3-(4-methoxybenzyl)-1,5-dimethyl-5-(2-methylbenzyl)imidazolidine-2,4-dione

To a solution of3-(4-methoxybenzyl)-5-(2-methylbenzyl)imidazolidine-2,4-dione (Example2.46c) (0.89 g, 2.74 mmol) in 7 mL DMF was added NaH (0.30 g, 8.23mmol). The mixture was stirred for 0.5 h at ambient temperature thenmethyl iodide (0.7 mL, 10.94 mmol) was added neat via syringe. Thereaction was stirred for 12 h at ambient temperature when it wasdetermined to be complete by LCMS. The mixture was diluted with 25 mLH₂O and extracted with ethyl acetate (3×10 mL). The combined organicphases were washed with H₂O (1×10 mL), and brine (1×10 mL) and driedwith Na₂SO₄ and the solvent was removed. The compound was dissolved in aminimum amount of DCM and loaded onto a 40 g Silicycle column purgedwith hexanes. A gradient from 0 to 70% ethyl acetate:hexanes was run toafford the desired product as a yellow oil (0.70 g, 73%). ¹H NMR (400MHz, DMSO-d₆) δ 7.15-7.07 (m, 2H), 7.00-6.96 (m, 1H), 6.85-6.83 (m, 1H),6.86-6.66 (m, 2H), 6.55-6.53 (m, 2H), 4.32 (d, J=15.4 Hz, 1H), 4.20 (d,J=15.4 Hz, 1H), 3.70 (s, 3H), 3.08 (d, J=14.6 Hz, 1H), 3.00 (d, J=14.6Hz, 1H), 2.93 (s, 3H), 2.24 (s, 3H), 1.47 (s, 3H); MS 353 (MH⁺).

Example 2.46c:3-(4-methoxybenzyl)-5-(2-methylbenzyl)imidazolidine-2,4-dione

To a suspension of (S)-5-(2-methylbenzyl)imidazolidine-2,4-dione(Example 2.46d) (0.73 g, 3.6 mmol) and K₂CO₃ (0.54 g, 3.9 mmol) in 2 mLDMF was added 1-(chloromethyl)-4-methoxybenzene (0.53 mL, 3.9 mmol). Thereaction was stirred for 12 h at ambient temperature where it wasdetermined to be complete by TLC. 10 mL H₂O was added with stirring andthe white precipitate was collected by vacuum filtration to afford thedesired product (0.9 g, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H),7.14-7.11 (m, 3H), 7.08-7.03 (m, 1H), 6.93-6.90 (m, 2H), 6.81-6.77 (m,2H), 4.45-4.31 (m, 3H), 3.72 (s, 3H), 3.04 (dd, J=14.4, 4.7 Hz, 1H),2.93 (dd, J=14.4, 6.3 Hz, 1H), 2.27 (s, 3H); MS 325 (MH⁺).

Example 2.46d: (S)-5-(2-methylbenzyl)imidazolidine-2,4-dione

To a 50 mL round bottom flask was added (S)-2-amino-3-(o-tolyl)propanoicacid (0.94 g, 5.30 mmol). 2M HCl (2.65 mL, 5.3 mmol) was added followedby 8 mL H₂O. The mixture was stirred with gentle heating untilhomogeneous. KOCN was added portion-wise as a solid. Stir at reflux for2 h. Cool to room temperature and add concentrated HCl until the pH isapproximately 2. Stir the suspension at reflux for 3 h. The reaction wascooled to room temperature and the precipitate was filtered and dried toafford the desired product as an off white solid (0.73 g, 67%). ¹H NMR(400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 7.92 (s, 1H), 7.17-7.09 (m, 4H),4.32-4.29 (m, 1H), 3.01 (dd, J=14.4, 4.7 Hz, 1H), 2.86 (dd, J=14.4, 6.9Hz, 1H), 2.28 (s, 3H).

Example 2.47:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (230 mg, 1.09 mmol)(Example 2.47a) and 2-bromo-1-phenylethanone (258 mg, 1.30 mmol) toobtain the desired product (75 mg, 21%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.95 (d, J=8 Hz, 2H), 7.49 (t, J=4 Hz, 2H), 8.30 (m,2H), 4.91 (s, 2H), 2.91 (s, 3H), 1.66 (m, =7H), 1.46 (s, 3H), 1.04 (m,4H). MS 329 (MH⁺).

Example 2.47a: 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-cyclohexyl-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(12.4 mmol, 4.1 g) (Example 2.47b) and a solution of ammonium ceriumnitrate (17.6 g, 32.2 mmol) in water (92 mL) to obtain the desiredproduct (2.1 g, 80%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.79 (s, 1H), 2.03 (s, 3H), 1.59 (m, 6H), 1.40 (s, 3H), 0.88 (m, 5H). MS211 (MH⁺).

Example 2.47b:5-cyclohexyl-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-cyclohexyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.47c) (16 mmol, 5 g) and MeI (18.9 mmol, 1.17 mL) to obtainthe desired product (4.5 g, 85%). ¹H NMR is consistent with thestructure. MS 331 (MH⁺).

Example 2.47c:5-cyclohexyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46c starting from5-cyclohexyl-5-methylimidazolidine-2,4-dione (3.8 g, 19.3 mmol) (Example2.47d) and para-methoxyl benzyl chloride (3.2 mL, 23.6 mmol) to obtainthe desired product (6 g, 98%) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆)δ 7.30 (d, J=2H), 6.82 (d, 2H), 5.39 (s, 1H), 4.56 (s, 2H), 3.78 (s,3H), 1.60 (m, 5H), 1.35 (s, 3H), 0.80 (s, 6H). MS 317 (MH⁺).

Example 2.47d: 5-cyclohexyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-cyclohexylethanone (3 g, 23.8 mmol), (NH₄)₂CO₃ (7.1 g, 73.9 mmol), andKCN (1.28 g, 26.1 mmol) to obtain the desired product (3.5 g, 75%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.89 (s, 1H),1.75-1.58 (m, 4H), 1.50-1.38 (m, 2H), 1.21 (s, 3H), 1.19-1.11 (m, =2H),1.08-0.90 (m, 3H). MS 197 (MH⁺).

Example 2.48:5-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.54a) (1.04 g, 4.70 mmol), K₂CO₃ (0.97 g, 7.00 mmol), and 5 mLDMF. The suspension was stirred at ambient temperature, and2-bromo-1-(1H-pyrrol-2-yl)ethanone (Example 2.48a) (0.88 g, 7.70 mmol)was added as a solid. The reaction was stirred for 3 hours when it wasdetermined to be complete by LCMS. 15 mL water was added and the mixturewas extracted with ethyl acetate (3×15 mL). The combined organic layerswere washed with water (1×30 mL), brine (1×30 mL) and dried with Na₂SO₄.The solvent was removed and the residue was concentrated into a 40 mLvial. The vial contained approximately 1 gram of crude material. Theresidue was dissolved in a total of 20 mL of acetonitrile and water andpurified by HPLC utilizing a 40 minute method to afford the titlecompound (0.085 g) as a white solid. The residue was concentrated fromethanol 3 times. Two diastereomers separated during chromatography. Thefirst compound to elute, shown here, is the most potent. ¹H-NMR (400MHz, DMSO-d₆) δ 12.04 (s, 1H) 7.19-7.16 (m, 2H), 6.26-6.24 (m, 1H), 4.68(s, 2H), 2.80 (s, 3H), 2.40 (s, 1H), 2.14 (s, 1H), 1.84-1.80 (m, 1H),1.49-1.47 (m, 2H), 1.42 (s, 3H), 1.33-1.31 (m, 2H), 1.27-1.25 (m, 1H),1.16-1.13 (m, 2H), 1.00-0.98 (m, 1H); MS 330 (MH⁺).

Example 2.48a: 2-bromo-1-(1H-pyrrol-2-yl)ethanone

To a solution of bromoacetyl bromide (5 mL, 56.4 mmol) in 150 mLchloroform was added a solution of pyrol (2.6 mL, 37.5 mmol) and2,6-lutidine (9 mL, 75 mmol) in 40 mL chloroform via addition funnel.The reaction was stirred for 24 h at ambient temperature. The reactionwas washed with 1 M HCl (1×100 mL) and saturated sodium bicarbonate(1×100 mL) and dried with Na₂SO₄. The solvent was evaporated and theresidue was purified by column chromatography utilizing a Silicyclecolumn (120 g) and elution with DCM. The title compound was isolated 2.7g (25%) as a dark grey solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H),7.19-7.15 (m, 2H), 6.25-6.23 (m, 1H), 4.54 (s, 2H).

Example 2.49:5-cyclohexyl-3-(2-(3,5-dihydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner to Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (47a) (100.0 mg, 476umol), and 2-bromo-1-(3,5-dihydroxyphenyl)ethanone (Example 2.49a) (124mg, 537 umol), to obtain the desired product (61.9 mg, 36%). ¹H NMR (400MHz, d₆-DMSO) δ 9.78 (s, 2H), 6.82 (d, J=2.2 Hz, 2H), 6.52 (t, J=2.2 Hz,1H), 4.80 (d, J=18.2 Hz, 1H), 4.75 (d, J=18.1 Hz, 1H), 2.81 (s, 3H),1.79-1.65 (m, 4H), 1.65-1.56 (m, 2H), 1.37 (s, 3H), 1.36-1.27 (m, 1H),1.26-1.12 (m, 2H), 1.11-1.01 (m, 1H), 0.98-0.86 (m, 1H). MS 361 (MH⁺).

Example 2.49a: 2-bromo-1-(3,5-dihydroxyphenyl)ethanone

Copper bromide (3.17 g, 13.5 mmol) was suspended in EtOAc (26 mL) andcommercially available 1-(3,5-dihydroxyphenyl)ethanone (1.0 g, 6.6 mmol)dissolved in DCM (12 mL) was added. The reaction medium was heated at70° C. for 16 hours and filtered hot through a celite pad further washedwith EtOAc. Solvents were evaporated and the brown residue was purifiedby flash-chromatography using a Silicycle column (80 g) and a DCM/EtOAcgradient as eluant, to obtain after evaporation of solvents and dryingthe desired product (896.1 mg, 59%). ¹H NMR (400 MHz, d₆-DMSO) δ 6.82(d, J=2.2 Hz, 2H), 6.49 (t, J=2.2 Hz, 1H), 5.76 (s, 2H), 4.80 (s, 2H).MS no ionization.

Example 2.50:3-(2-(3-aminophenyl)-2-oxoethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

In a small round-bottom flask flushed with N₂, were added5-cyclohexyl-1,5-dimethyl-3-(2-(3-nitrophenyl)-2-oxoethyl)imidazolidine-2,4-dione(Example 2.50a) (100.0 mg, 268 umol) in EtOH/H₂O (1.1 mL/1.1 mL)followed by NH₄Cl (100.0 mg, 1.87 mmol) and iron powder (200.0 mg, 3.58mmol). The reaction medium was refluxed for 2 hours, and filteredthrough a celite pad. The filtrate was concentrated under vacuum andpartitioned between EtOAc and brine and extracted with EtOAc (3×10 mL).Combined organic phases were dried over MgSO₄, and solvents wereevaporated. The residue was purified by flash chromatography (12 gSilicycle column and DCM/EtOAc gradient as eluant), followed by a 40minutes preparative HPLC run using a H₂O/ACN gradient as eluant toobtain the desired product. ¹H NMR (400 MHz, d₆-DMSO) δ 7.19-7.18 (m,2H), 7.13-7.12 (m, 1H), 6.87-6.84 (m, 1H), 5.39 (s, 2H), 4.79 (s, 2H),2.79 (s, 3H), 1.74-1.68 (m, 4H), 1.63-1.56 (m, 2H), 1.38 (s, 3H),1.36-1.28 (m, 1H), 1.24-1.13 (m, 2H), 1.10-0.99 (m, 1H), 0.98-0.92 (m,1H). MS 344 (MH⁺).

Example 2.50a:5-cyclohexyl-1,5-dimethyl-3-(2-(3-nitrophenyl)-2-oxoethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (500.0mg, 2.38 mmol), and 2-bromo-1-(3-nitrophenyl)ethanone (641.0 mg, 2.627mmol). The residue was purified by flash-chromatography using aSilicycle column (120 g) and a Hexanes/EtOAc gradient as eluant, toobtain after evaporation of solvents and drying the desired product(765.7 mg, 86%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.73-8.70 (m, 1H),8.55-8.51 (m, 1H), 8.49-8.45 (m, 1H), 7.88 (t, J=8.0 Hz, 1H), 5.10 (s,2H), 2.82 (s, 3H), 1.79-1.66 (m, 4H), 1.66-1.54 (m, 2H), 1.39 (s, 3H),1.37-1.28 (m, 1H), 1.25-1.12 (m, 2H), 1.09-1.00 (m, 1H), 0.96-0.88 (m,1H). MS 374 (MH⁺).

Example 2.51:5-((1S,2S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-((1S,2S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.51a) (109 mg, 0.32 mmol) and methyliodide (22 uL, 0.35 mmol)to obtain the desired product as a white powder (70 mg, 62% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.01 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H),7.55 (t, J=8 Hz, 2H), 6.11 (t, J=8 Hz, 1H), 5.95 (t, J=8 Hz, 1H), 4.88(q, J=16 Hz, J=36 Hz, 2H), 2.79 (s, 3H), 2.48 (m, 1H), 2.29 (m, 1H),2.15 (t, J=8 Hz, 1H), 1.39-1.62 (m, 4H), 1.28 (s, 3H), 1.12 (m, 2H). MS353 (MH⁺).

Example 2.51a:5-((1S,2S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-5-methylimidazolidine-2,4-dione (Example2.51b) (220 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol). Theproduct eluted first (Rf=0.55) on a flash chromatography 120 g Silicyclecolumn and, after evaporation of solvents, was obtained as a whitepowder (109 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (d, J=8 Hz,2H), 7.95 (s, 1H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 6.16 (m,2H), 4.852 (d, J=1.6 Hz, 2H), 2.66 (m, 1H), 1.99 (t, J=8 Hz, 1H),1.39-1.56 (m, 4H), 1.30 (s, 3H), 1.09 (m, 3H). MS 338 (MH⁺).

Example 2.51b:5-(bicyclo[2.2.2]oct-5-en-2-yl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(bicyclo[2.2.2]oct-5-en-2-yl)ethanone (Example 2.51c) (1 g, 6.67mmol)) to obtain product as a white powder of mixture of 2 pairs ofdiastereomers (1.3 g, 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (bs,1H), 7.42-7.56 (2s, 1H), 6.10 (m, 1.4H), 5.96 (t, J=8 Hz, 0.6H), 2.60(m, 0.4H), 2.44 (m, 0.6H), 2.15 (m, 0.6H), 1.89 (m, 1H), 1.67 (t, J=8Hz, 1H), 1.36-1.51 (m, 2.6H), 1.18 (s, 1H), 1.12 (m, 2.4H), 1.06 (s,2H), 0.93 (m, 0.4H). MS 221 (MH⁺).

Example 2.51c: 1-(bicyclo[2.2.2]oct-5-en-2-yl)ethanone

To the solution of cyclohexadiene (1.78 mL, 18.75 mmol) in 15 mL of dryDCM cooled to 0° C. under N₂ atmosphere was added methylvinylketone(7.63 mL, 93.75 mmol), following SnCl₄ (2.19 mL, 18.75 mmol) dropwiseover 30 min period. The reaction mixture was stirred at 0° C. for 1 h,then poured in to 100 mL of saturated NaHCO₃ and extracted with DCM(3×50 mL). The combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 120 g Silicycle column and a Hexanes/Et₂Ogradient as eluant to obtain the pure ketone (2.1 g, 75%) as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 6.27 (t, J=8 Hz, 1H), 6.10 (t, J=8 Hz,1H), 2.90 (m, 1H), 2.67 (t, J=8 Hz, 1H), 2.60 (m, 1H), 2.11 (s, 3H),1.66 (m, 2H), 1.59 (m, 1H), 1.50 (m, 1H), 1.28 (m, 1H), 1.24 (m, 1H). MSN/A (MH⁺).

Example 2.52:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(thiophen-3-yl)ethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL), 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.47a) (150 mg, 714 umol), and cooled to 0° C. Next, NaH (35mg, 856 umol), and 2-bromo-1-(thiophen-3-yl)ethanone (175 mg, 856 umol)were added and the reaction medium was allowed to warm to roomtemperature and stirred vigorously for 1.5 hr. The solution wasextracted with H₂O/EtOAc (3×) and the combined organic phases werewashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography using a 12 g Silicyclecolumn and EtOAc/Hex gradient as eluant to obtain the pure desiredproduct (20 mg, 8.4%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ8.15 (dd, J=2.8, 1.3 Hz, 1H), 7.56 (dd, J=5.1, 1.3 Hz, 1H), 7.37 (dd,J=5.1, 2.9 Hz, 1H), 4.81 (s, 2H), 2.91 (s, 3H), 1.89-1.64 (m, 6H),1.54-1.42 (m, 1H), 1.48 (s, 3H), 1.29-0.99 (m, 4H).

Example 2.53:5-((1s,4s)-bicyclo[2.2.2]octan-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-((1S,4S)-bicyclo[2.2.2]octan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.53a) (60 mg, 0.18 mmol) and methyliodide (12 uL, 0.19 mmol)to obtain product as a white powder (38 mg, 62% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.01 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz,2H), 4.97 (s, 2H), 2.89 (s, 3H), 2.02 (t J=8 Hz, 1H), 1.82 (m, 1H), 1.61(m, 3H), 1.28-1.46 (m, 8H), 1.38 (s, 3H). MS 355 (MH⁺).

Example 2.53a:5-((1S,4S)-bicyclo[2.2.2]octan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(bicyclo[2.2.2]octan-2-yl)-5-methylimidazolidine-2,4-dione (Example2.53b) (222 mg, 1 mmol) and 2-bromoacetophenone (219 mg, 1.1 mmol). Whenpurified by flash chromatography the product eluted second (R_(f)=0.5)on a 120 g Silicycle column and, after evaporation of solvents, wasobtained as a white powder (65.8 mg, 19% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.60 (s, 1H), 8.01 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H),7.55 (t, J=8 Hz, 2H), 4.90 (s, 2H), 1.94 (t, J=8 Hz, 1H), 1.85 (m, 1H),1.67 (m, 2H), 1.35-1.50 (m, 9H), 1.28 (s, 3H). MS 341 (MH⁺).

Example 2.53b:5-(bicyclo[2.2.2]octan-2-yl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(bicyclo[2.2.2]octan-2-yl)ethanone (Example 2.53c) (1 g, 6.67 mmol) toobtain product as a white powder and a mixture of 2 pairs ofdiastereomers (1.15 g, 78% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.03(bs, 1H), 7.68 and 8.05 (2s, 1H), 2.380 (m, 0.5H), 2.06 (m, 0.5H), 1.95(m, 0.5H), 1.59-1.82 (m, 4H), 1.55 (m, 2H), 1.31-1.53 (m, 5.5H), 1.305(d, J=4 Hz, 3H), 1.20 (s, 1.5H), 1.16 (s, 3H). MS 221 (MH⁺).

Example 2.53c: 1-(bicyclo[2.2.2]octan-2-yl)ethanone

A solution of 1-(bicyclo[2.2.2]oct-5-en-2-yl)ethanone (Example 2.51c) (1g, 6.67 mmol) in 50 mL of EtOAc was hydrogenated on 10% Pd/C (57 mg) inParr shaker at 20 psi at room temperature for 5 h. Then reaction mixturewas filtered trough Celite pad and the filtrate was concentrated invacuum to obtain 90% clean ketone as a colorless oil (1 g, 100%). ¹H NMR(400 MHz, CDCl₃) δ 2.64 (m, 1H), 2.13 (s, 3H), 2.04 (m, 1H), 1.94 (m,1H), 1.65 (m, 3H), 1.46-1.55 (m, 4H), 1.37-1.43 (m, 3H). MS N/A (MH⁺).

Example 2.54:5-((bicyclo[2.2.1]heptan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.54a) (0.86 g, 3.87 mmol), K₂CO₃ (0.80 g, 5.80 mmol), and 3 mLDMF. The suspension was stirred at 50° C. and a solution of2-bromo-1-(3-hydroxyphenyl)ethanone (0.83 g, 3.87 mmol) in 1 mL of DMFwas added drop-wise over 5 minutes. The reaction was stirred for 2 hourswhen it was determined to be complete by LCMS. 10 mL of water was addedand the mixture was extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with water (1×20 mL), brine (1×20 mL) anddried with Na₂SO₄. The solvent was evaporated and the residue purifiedby column chromatography utilizing an 40 g Silicycle column and elutionwith 0-40% ethyl acetate/hexanes to afford a mixture of diastereomers.The diastereomers were separated by HPLC utilizing a 40 minute method toafford the title compound (0.100 g) as a white solid. The compound wasconcentrated from ethanol three times. The compound was thenrecrystallized from ethanol/water to afford 84 mg of the title compoundas a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 7.51-7.49(m, 1H), 7.39-7.35 (m, 1H), 7.33-7.32 (m, 1H), 7.10-7.08 (m, 1H), 4.89(s, 2H), 2.81 (s, 3H), 2.37 (s, 1H), 2.17 (s, 1H), 1.84-1.81 (m, 1H),1.49-1.47 (m, 2H), 1.43 (s, 3H), 1.37-1.32 (m, 1H), 1.27-1.14 (m, 4H),1.02-0.99 (m, 1H); MS 357 (MH⁺).

Example 2.54a:5-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethylimidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.54b) (2.04 g, 5.96 mmol), 15 mL acetonitrile, 6 mL water andceric ammonium nitrate (5.30 g 9.67 mmol). The reaction was stirred 24hours at ambient temperature were it was determined to be ca. 85%complete by LCMS. The solvent was removed and the residue was dissolvedin 50 mL ethyl acetate. The organic layer was washed with 1 M HCl (1×25mL), water (1×25 mL), brine (1×25 mL) and dried with Na₂SO₄. The solventwas evaporated, and the resulting residue was purified by columnchromatography utilizing a Silicycle column (40 g) and elution with10-40% ethyl acetate/hexanes. The title compound was isolated (1.13 g,84%) as a mixture of diastereomers. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.81(s, 2H), 2.71-2.70 (m, 6H), 2.23-2.21 (m, 2H), 2.14 (s, 1H), 1.87-1.71(m, 4H) 1.47-1.45 (m, 4H), 1.34-1.11 (m, 14H), 1.03-0.94 (m, 3H); MS 223(MH⁺).

Example 2.54b:5-bicyclo[2.2.1]heptan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazo-lidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-3-(4-methoxybenzyl)-5-methylimidazodine-2,4-dione (Example 2.54c) (3.4 g, 10.4 mmol), 10 mL of anhydrousDMF, and NaH (0.7 g, 20.7 mmol). The reaction was stirred ambienttemperature for 30 minutes and methyl iodide (2 mL, 31.2 mmol) wasadded. The reaction was stirred for one hour at ambient temperature whenit was determined to by complete by LCMS and TLC. 30 mL water was addedthe mixture was extracted with ethyl acetate (3×10 mL). The combinedextracts were washed with water (1×20 mL), brine (1×20 mL) and driedwith Na₂SO₄. The solvent was evaporated, and the resulting residue waspurified by column chromatography utilizing a Silicycle column (80 g)and elution with 0-50% ethyl acetate/hexanes. The title compound wasisolated 2.0 g (57%) as a mixture of diastereomers. ¹H-NMR (400 MHz,DMSO-d₆) δ 7.19-7.16 (m, 4H), 6.89-6.86 (m, 4H), 4.46 (s, 4H), 3.72-3.71(m, 6H), 2.78 (s, 3H), 2.76 (s, 3H), 2.21 (s, 1H), 2.14 (s, 1H), 2.0 (s,1H), 1.83-1.72 (m, 4H), 1.44-1.35 (m, 7H), 1.27-1.23 (m, 5H), 1.14-1.04(m, 5H), 0.95-0.90 (m, 2H), 0.82-0.77 (m, 1H), 0.72-0.69 (m, 1H); MS 343(MH⁺).

Example 2.54c:5-bicyclo[2.2.1]heptan-2-yl)-3-(4-methoxybenzyl)-5-methyl-imidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added5-bicyclo[2.2.1]heptan-2-yl)-5-methylimidazolidine-2,4-dione (Example2.42b) (2.67 g, 12.8 mmol), 7 mL DMF, K₂CO₃ (2.65 g, 19.2 mmol) and4-methoxybenzyl chloride (1.75 mL, 12.8 mmol). The vial was sealed andthe reaction mixture was stirred at ambient temperature for 12 hrs. Thereaction was quenched with water (25 mL) and extracted with EtOAc (3×20mL). The organic layers were combined, washed with water (40 mL), brine(40 mL), and dried over Na₂SO₄. The solvent was evaporated, and theresulting residue was purified by column chromatography utilizing aSilicycle column (40 g) and elution with 0-50% ethyl acetate/hexanes.The title compound was isolated 3.4 g (81%) as a mixture ofdiastereomers. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.27 (s, 1H)7.23-7.15 (m, 4H), 6.89-6.86 (m, 4H), 4.45 (s, 2H), 4.42-4.40 (m, 2H),3.73-3.72 (m, 6H), 2.15-2.10 (m, 3H), 1.72-1.64 (m, 2H), 1.59-1.58 (m,1H), 1.44-1.24 (m, 1H), 1.14-1.01 (m, 9H), 0.96-0.88 (m, 2H); MS 329(MH⁺).

Example 2.55:5-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

The title compound was isolated during the purification of 54. Compound55 eluted after compound 54 on the HPLC during the separation of thediastereomers. The procedure is identical to that of 54. ¹H-NMR (400MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.52-7.49 (m, 1H), 7.39-7.35 (m, 1H),7.33-7.32 (m, 1H), 7.10-7.07 (m, 1H), 4.88 (s, 2H), 2.83 (s, 3H), 2.21(s, 1H), 2.01 (s, 1H), 1.89-1.85 (m, 2H), 1.48-1.47 (m, 2H), 1.35-1.29(m, 4H), 1.20-1.14 (m, 3H), 0.97-0.95 (m, 1H); MS 357 (MH⁺).

Example 2.56:5-cyclohexyl-3-(2-(4-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (102.3mg, 476 umol), and commercially available2-chloro-1-(4-hydroxyphenyl)ethanone (90.0 mg, 528 umol), to obtain thedesired product (47.6 mg, 28%). ¹H NMR (400 MHz, d₆-DMSO) δ 10.47 (s,1H), 7.91 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.85 (d, J=18.1 Hz,1H), 4.80 (d, J=18.0 Hz, 1H), 2.81 (s, 3H), 1.78-1.66 (m, 4H), 1.65-1.57(m, 2H), 1.38 (s, 3H), 1.36-1.27 (m, 1H), 1.25-1.13 (m, 2H), 1.10-1.01(m, 1H), 1.00-0.88 (m, 1H). MS 345 (MH⁺).

Example 2.57:5-((1S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-((1S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.57a) (191 mg, 0.56 mmol) and methyliodide (39 uL, 0.62 mmol)to obtain product as a white powder (118 mg, 60% yield). ¹H NMR (400MHz, DMSO-d₆) δ 8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.56 (t, J=8Hz, 2H), 6.19 (t, J=8 Hz, 1H), 5.98 (t, J=8 Hz, 1H), 4.955 (q, J=16 Hz,J=30 Hz, 2H), 2.71 (s, 3H), 2.51 (m, 2H), 2.13 (t, J=8 Hz, 1H), 1.70 (t,J=8 Hz, 1H), 1.43 (m, 2H), 1.29 (s, 3H), 1.16 (m, 3H). MS 353 (MH⁺).

Example 2.57a:5-((1S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-5-methylimidazolidine-2,4-dione (Example2.51b) (220 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol). Whenpurified by flash chromatography the product eluted second on a 120 gSilicycle column (Rf=0.5) and, after evaporation of solvents, wasobtained as a white powder (191.3 mg, 57% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.07 (s, 1H), 8.03 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H),7.56 (t, J=8 Hz, 2H), 6.15 (t, J=8 Hz, 1H), 6.05 (t, J=8 Hz, 1H), 4.91(s, 2H), 2.52 (m, 1H), 2.41 (m, 1H), 2.02 (t, J=8 Hz, 1H), 1.72 (t, J=8Hz, 1H), 1.41 (m, 2H), 1.17 (s, 3H), 1.09 (m, 3H). MS 338 (MH⁺).

Example 2.58:5-cyclohexenyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-cyclohexenyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.58a) (92.2 mg, 295 umol) and MeI (50.0 uL, 803 umol) toobtain the desired product (28.1 mg, 29%) as an oily film. ¹H NMR (400MHz, DMSO-d₆) δ 7.96-7.94 (m, 2H), 7.62-7.59 (m, 1H), 7.50-7.47 (m, 2H),5.93 (s, br, 1H), 4.93 (s, 2H), 2.79 (s, 3H), 2.20-2.08 (m, 2H),1.99-1.87 (m, 2H), 1.74-1.65 (m, 2H), 1.65-1.53 (m, 2H), 1.58 (s, 3H).MS 327 (MH⁺).

Example 2.58a:5-cyclohexenyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting froma crude mixture containing5-cyclohexenyl-5-methylimidazolidine-2,4-dione (Example 2.58b) (300 mg,1.54 mmol) and 2-bromo-1-phenylethanone (378 mg, 1.90 mmol) to obtainthe desired product (92.2 mg, 19% over 2 steps 58a and 58b).

MS 313 (MH⁺).

Example 2.58b: 5-cyclohexenyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-cyclohexenylethanone (1 g, 8.1 mmol) to obtain product that was usedas a crude mixture without further purification.

Example 2.59:3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione (Example2.59a) (105 mg, 0.5 mmol) and 2-bromo-1-(3-hydroxyphenyl)ethanone (107mg, 0.5 mmol). Gives 81.6 mg (47% yield) of a white powder of mixture of4 pairs of diastereomers. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (bs, 1H),7.47 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J=8Hz, 1H), 4.87 (t, J=4 Hz, 2H), 2.80-2.86 (4s, 3H), 2.00-2.4 (m, 1H),1.82 (m, 2H), 1.65 (m, 2H), 1.49 (m, 1H), 1.39-1.41 (4s, 3H), 1.35 (m,1H), 1.17 (m, 1H), 0.66-0.98 (4d, J=8 Hz, 3H). MS 345 (MH⁺).

Example 2.59a:1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from3-(4-methoxybenzyl)-1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione(Example 2.59b) (818 mg, 2.48 mmol) and a solution of ammonium ceriumnitrate (3.53 g, 6.45 mmol) in water (15 mL) to obtain product as awhite powder of mixture of 4 pairs of diastereomers (435 mg, 83% yield).¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (bs, 1H), 2.69-2.75 (4s, 3H),1.96-2.19 (m, 1H), 1.80 (m, 2H), 1.65 (m, 2H), 1.44 (m, 2H), 1.28-1.31(4s, 3H), 1.14 (m, 1H), 0.63-0.93 (4d, J=8 Hz, 3H). MS 211 (MH⁺).

Example 2.59b:3-(4-methoxybenzyl)-1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from3-(4-methoxybenzyl)-5-methyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione(Example 2.59c) (913 mg, 2.88 mmol) and methyl iodide (270 uL, 4.33mmol) to obtain product as a colorless oil of mixture of 4 pairs ofdiastereomers (818 mg, 86% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 6.87 (d,J=8 Hz, 2H), 6.56 (d, J=8 Hz, 2H), 4.15 (s, 2H), 3.40 (s, 3H), 2.47-2.52(4s, 3H), 1.75-1.90 (m, 1H), 1.55 (m, 1H), 1.32 (m, 2H), 1.13 (m, 2H),1.00-1.04 (4s, 3H), 0.95 (m, 0.5H),0.80 (m, 1H), 0.66 (m, 0.5H),0.01-0.56 (4d, J=8 Hz, 3H). MS 331 (MH⁺).

Example 2.59c:3-(4-methoxybenzyl)-5-methyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45c starting from5-methyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione (Example 2.59d)(585 mg, 2.69 mmol) and 4-methoxybenzyl chloride (438 uL, 3.22 mmol) toobtain product as a white powder of mixture of 4 pairs of diastereomers(850 mg, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.15 (d,J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 4.41 (s, 2H), 3.70 (s, 3H), 1.96-2.25(m, 1H), 1.52-1.80 (m, 3H), 1.39 (m, 3H), 1.22-1.30 (4s, 3H), 1.13 (m,1H), 0.47-0.72 (4d, J=8 Hz, 3H). MS 317 (MH⁺).

Example 2.59d: 5-methyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2-methylcyclopentyl)ethanone (Example 2.59e) (988 mg, 7.84 mmol) toobtain product as a white powder of mixture of 4 pairs of diastereomers(790 mg, 51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (bs, 1H), 7.90(s, 1H), 1.39-1.86 (m, 8H), 1.19-1.26 (4s, 3H), 1.13 (m, 1H), 0.71-0.98(4d, J=8 Hz, 3H). MS 197 (MH⁺).

Example 2.59e: 1-(2-methylcyclopentyl)ethanone

To 1 g (7.81 mmol) of 2-methylcyclopentanecarboxylic acid in 10 mL dryether under N₂ atmosphere at −20° C. was added dropwise over 20 minutes1.5 M ethereal solution of methyllitium (10.42 mL, 15.62 mmol). Reactionmixture was stirred at 0° C. for 30 min, then gradually warmed up toroom temperature and stirred 18 h. Resulting cloudy solution was pouredin to mixture of 50 mL ice-water and 50 mL of 1N HCl and then productwas extracted with ether (3×50 mL). Organic fractions were washed withwater, saturated NaHCO₃, water, dried over MgSO₄ and concentrated invacuum yielded 988 mg of 1-(2-methylcyclopentyl)-ethanone as a colorlessoil consisting of two pairs of diastereomers (2:1 ratio by NMRanalysis). Crude ketone was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95 (m, 0.2H), 2.38 (m,0.8H), 2.075 (d, J=4 Hz, 3H), 2.03 (m, 1H), 1.76 (m, 2H), 1.54 (m, 3H),1.3 (m, 0.4H), 1.14 (m, 0.6H), 0.69-0.97 (2d, J=8 Hz, 3H). MS N/A (MH⁺).

Example 2.60:3-(2-(3-hydroxyphenyl)-2-oxoethyl)-5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (3.0 mL),5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione (Example 2.60a)(234 mg, 1 mmol), and at 0° C. NaH (120 mg, 3 mmol), and2-bromo-1-(3-hydroxylphenyl)ethanone (256 mg, 1.2 mmol). The reactionmedium was stirred vigorously at room temperature overnight, poured inwater (20 mL) and extracted with EtOAc (3×20 mL). Combined organicphases were washed with brine and dried over MgSO₄, and solvents wereevaporated. The residue was purified by HPLC to obtain the pure desiredproduct (80 mg, 22%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.45(dt, J=7.6, 1.7 Hz, 2H), 7.39 (ddd, J=8.3, 7.5, 1.6 Hz, 1H), 7.31-7.26(m, 3H), 7.07-7.00 (m, 2H), 6.91 (dd, J=8.3, 1.0 Hz, 1H), 6.87 (s, 1H),5.03 (s, 2H), 3.79 (s, 3H), 2.66 (s, 3H), 1.94 (s, 3H). MS 316 (MH⁺).

Example 2.60a: 5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione

In a N₂-flushed round-bottom flask, were added anhydrous CH₃CN (15 mL),3-(4-methoxybenzyl)-5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.0.60b) (531 mg, 1.5 mmol), and at 0° C. dropwise anice-cooled solution of ammonium cerium IV nitrate (2145.0 mg, 3.9 mmol)in H₂O (9 mL). The reaction medium was monitored by TLC, stirredvigorously at room temperature overnight, and extracted with brine/EtOAc(3×). Combined organic phases were washed again with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 40 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure desired product (168 mg, 48%). ¹HNMR is consistent with structure. MS 235 (MH⁺).

Example 2.60b:3-(4-methoxybenzyl)-5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (4.0 mL),3-(4-methoxybenzyl)-5-(2-methoxyphenyl)-5-methylimidazolidine-2,4-dione(Example 2.60c) (680 mg, 2 mmol), and NaH (100.0 mg, 2.5 umol), and MeI(186 uL, 3 mmol). The reaction medium was stirred vigorously at roomtemperature overnight, poured in water (20 mL) and extracted withH₂O/EtOAc (3×). Combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 40 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure desired product (566.4 mg, 80%).¹H NMR is consistent with structure. MS 355 (MH⁺).

Example 2.60c:3-(4-methoxybenzyl)-5-(2-methoxyphenyl)-5-methylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (10.0 mL),5-(2-methoxyphenyl)-5-methylimidazolidine-2,4-dione (Example 2.60d)(1980 mg, 9.0 mmol), K₂CO₃ (2.48 g, 18 mmol), KI (180 mg, 1.1 mmol) and1-(bromomethyl)-4-methoxybenzene (1.35 mL, 10 mmol). The reaction mediumwas stirred vigorously at room temperature overnight, poured in water(100 mL) and extracted with H₂O/EtOAc (3×). Combined organic phases werewashed with brine and dried over MgSO₄, and solvents were evaporated.The residue was purified by flash chromatography using a 40 g Silicyclecolumn and a Hexanes/EtOAc gradient as eluant to obtain the pure desiredproduct (2.45 g, 80%). ¹H NMR is consistent with structure. MS 341(MH⁺).

Example 2.60d: 5-(2-methoxyphenyl)-5-methylimidazolidine-2,4-dione

In a 40 mL roundbottom vial, were added H₂O (20 mL),2-methoxyacetophenone (1.5 g, 10 mmol) in EtOH (10 mL), (NH₄)₂CO₃ (3.36g, 35 mmol), and KCN (1.0.2 g, 15 mmol) in H₂O (10 mL) dropwise over afew minutes. The reaction mixture was stirred and heated at 50° C. untiljudged complete by LCMS analysis. The reaction medium was allowed tocool down, the obtained white precipitate was filtered and washed with alittle cold H₂O and dried to obtain the desired pure product (2.0 g,90%). ¹H NMR is consistent with structure. MS 221 (MH⁺).

Example 2.61:5-((1R,2S,4R)-bicyclo[2.2.2]octan-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-((1R,2S,4S)-bicyclo[2.2.2]octan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.61a) (65.8 mg, 0.19 mmol) and methyl iodide (13 uL, 0.21mmol) to obtain product as a white powder (40 mg, 62% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.01 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55(t, J=8 Hz, 2H), 4.95 (s, 2H), 2.75 (s, 3H), 2.08 (t J=8 Hz, 1H), 1.98(t J=8 Hz, 1H), 1.57 (m, 2H), 1.47 (m, 4H), 1.37 (s, 3H), 1.24-1.37 (m,5H). MS 355 (MH⁺).

Example 2.61a:5-((1R,2S,4R)-bicyclo[2.2.2]octan-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(bicyclo[2.2.2]octan-2-yl)-5-methylimidazolidine-2,4-dione (Example2.53b) (222 mg, 1 mmol) and 2-bromoacetophenone (219 mg, 1.1 mmol). Whenpurified by flash chromatography the product eluted first (R_(f)=0.55)on a 120 g Silicycle column and, after evaporation of solvents, wasobtained as a white powder (60 mg, 18% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 8.27 (s, 1H), 8.01 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8Hz, 2H), 4.91 (s, 2H), 1.89 (t, J=8 Hz, 1H), 1.67 (m, 2H), 1.56 (m, 1H),1.35-1.50 (m, 8H), 1.33 (s, 3H), 1.28 (m, 1H). MS 341 (MH⁺).

Example 2.62:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (68 mg, 0.32 mmol)(Example 2.47a) and 2-chloro-1-(1H-pyrrol-2-yl)ethanone (55 mg, 0.38mmol) to obtain the desired product (21 mg, 20%) as a light purple oil.¹H NMR (400 MHz, DMSO-d₆) δ 9.345 (s, 1H), 7.045 (m, 1H), 6.991 (m, 1H),6.299 (m, 1H), 4.752 (s, 2H), 2.903 (s, 3H), 1.600 (m, 6H), 1.461 (s &m, 4H), 1.027 (m, 4H). MS 318 (MH⁺).

Example 2.63:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (266 mg, 1.26 mmol)(Example 2.47a) and 3-(bromoacetyl)-pyridine hydrobromide (424 mg, 1.5mmol) to obtain the desired product (60 mg, 14%) as a clear oil. ¹H NMR(400 MHz, DMSO-d₆) δ 9.187 (s, 1H), 8.827 (d, J=4.8 Hz, 1H), 8.222 (d,J=8 Hz 1H), 7.444 (dd, J=8.4 Hz & 4.4 Hz, 1H), 4.911 (s, 2H), 2.918 (s,3H), 1.657 (m, 6H), 1.485 (s & m, 4H), 1.029 (m, 4H). MS 330 (MH⁺).

Example 2.64:1,5-dimethyl-5-(2-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-methyl-5-(2-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.64a) (242 mg, 0.77 mmol) and methyl iodide (58 uL, 0.92 mmol)to obtain product as a white powder of mixture of 4 pairs ofdiastereomers (103.7 mg, 41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.02(d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.95 (s,2H), 2.81-2.86 (3s, 3H), 2.34 (m, 1H), 1.88 (m, 2H), 1.65 (m, 2H), 1.49(m, 2H), 1.37-1.43 (3s, 3H), 1.16 (m, 1H), 0.83-0.98 (3d, J=8 Hz, 3H).MS 329 (MH⁺).

Example 2.64a:5-methyl-5-(2-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-methyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione (Example 2.59d)(196 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol) to obtainproduct as a white powder of mixture of 4 pairs of diastereomers (242.7mg, 77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (bs, 1H), 8.03 (d, J=8Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 2H), 4.91 (d, J=8 Hz,2H), 1.96-2.19 (m, 1H), 1.80 (m, 2H), 1.65 (m, 2H), 1.48 (m, 2H),1.32-1.36 (3s, 3H), 1.17 (m, 1H), 1.03-0.78 (3d, J=8 Hz, 3H). MS 315(MH⁺).

Example 2.65:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione

To an oven-dried 150 mL pressure tube flushed under nitrogen, were addedhexobarbital (2.7 g, 11.4 mmol) in anhydrous DMF (34 mL) and at 0° C.sodium hydride (545 mg, 13.60 mmol), and the reaction medium was stirredvigorously for a few minutes at room temperature.2-Bromo-1-phenylethanone (2.77 g, 13.92 mmol) was then added at 0° C.,the pressure tube was sealed and the reaction medium stirred for 16hours at room temperature, followed by extraction with excess H₂O/EtOAc(3×). Combined organic phases were washed with brine, dried over MgSO₄,and solvents were evaporated. The residue was first purified by flashchromatography on silica gel and eluted with a Hexane/EtOAc gradient toobtain a yellow oil that precipitated out upon standing (4.14 g). Thematerial was then re-purified by flash chromatography on silica gel andeluted again with a Hexane/EtOAc gradient to obtain a colorless oil thatprecipitated out upon standing (3.77 g), and which was taken up in EtOH3 times successively, followed by evaporation of solvents in order toeliminate all traces of undesired solvents. Finally, the obtained whiteresidue was re-dissolved in a small amount of EtOH, heated fordissolution, and let stand for recrystallisation in the refrigeratorovernight, to obtain 3.16 g (78% yield) as a fluffy white powder. ¹H NMR(400 MHz, d₆-DMSO) δ 8.09-8.04 (m, 2H), 7.76-7.70 (m, 1H), 7.62-7.56 (m,2H), 5.81-5.76 (m, 1H), 5.36 (d, J=17.7 Hz, 1H), 5.26 (d, J=17.7 Hz,1H), 3.19 (s, 3H), 2.09-1.93 (m, 3H), 1.90-1.78 (m, 1H), 1.55 (s, 3H),1.63-1.44 (m, 4H). MS 355 (MH⁺)

Example 2.66:1,5-dimethyl-5-(2-methylcyclopentyl)-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from1,5-dimethyl-5-(2-methylcyclopentyl)imidazolidine-2,4-dione (Example2.59a) (105 mg, 0.5 mmol) and 2-bromo-1-(1H-pyrrol-2-yl)ethanone(Example 2.48a) (103 mg, 0.55 mmol) to obtain product as a white powderof mixture of 4 pairs of diastereomers (136 mg, 86% yield). ¹H NMR (400MHz, DMSO-d₆) δ 11.99 (bs, 1H), 7.15 (s, 2H), 6.22 (s, 1H), 4.65 (s,2H), 2.79-2.85 (4s, 3H), 2.36 (m, 1H), 1.88 (m, 2H), 1.65 (m, 2H), 1.46(m, 2H), 1.37-1.43 (4s, 3H), 1.16 (m, 1H), 0.66-0.98 (4d, J=8 Hz, 3H).MS 318 (MH⁺).

Example 2.67:5-((1R,4S)-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

The title compound was isolated during the purification of 48. Compound67 eluted after compound 48 on the HPLC during the separation of thediastereomers. The procedure is identical to that of 48. ¹H-NMR (400MHz, DMSO-d₆) δ 11.99 (s, 1H), 7.17 (s, 2H), 6.25 (s, 1H), 4.67 (s, 2H),2.82 (s, 3H), 2.20 (s, 1H), 2.03 (s, 1H), 1.89-1.84 (m, 2H), 1.47-1.44(m, 2H), 1.33-1.29 (m, 4H), 1.22-1.13 (m, 3H), 0.96-0.94 (m, 1H); MS 330(MH⁺).

Example 2.68:5-cyclohexyl-1-ethyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL),5-cyclohexyl-1-ethyl-5-methylimidazolidine-2,4-dione (Example 2.68a) (40mg, 178 umol) and the solution was cooled to 0° C. NaH (9 mg, 178 umol),and 2-bromo-1-phenylethanone (44 mg, 178 umol) were added, the ice bathwas removed and the reaction medium was stirred vigorously for 2 hrwarming to room temperature. The resulting mixture was extracted withH₂O/EtOAc (3×) and the combined organic phases were washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified bypreparative HPLC. The pure product was obtained as a clear oil (20 mg,33%).

¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=6.8 Hz, 2H), 7.59 (t, J=6.4 Hz,1H), 7.47 (t, J=5.6 Hz, 2H), 4.90 (s, 2H), 3.26 (d & sextet, J=44.8 Hz &7.2 Hz, 2H), 1.67-1.82 (m, 7H), 1.51 (s, 3H), 1.28 (t, J=6.4 Hz, 3H),1.03-1.24 (m, 4H) MS 343 (MH⁺).

Example 2.68a: 5-cyclohexyl-1-ethyl-5-methylimidazolidine-2,4-dione

In a N₂-flushed round-bottom flask, were added anhydrous CH₃CN (16 mL),5-cyclohexyl-1-ethyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.0.68b) (562 mg, 1.6 mmol), and the solution was cooled to 0°C. in an ice bath. An ice-cooled solution of ammonium cerium IV nitrate(2.3 g, 4.2 mmol) in H₂O (12 mL) was added dropwise and the reactionmedium was monitored by TLC. The solution was allowed to warm to roomtemperature with continued vigorous stirring overnight. Acetonitrile wasremoved in vacuo, the residue was treated with H₂O and 30% CH₃CN in DCM.The organic layer was dried, concentrated and purified by flashchromatography using a 40 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure product (300 mg, 83%). MS 225(MH⁺). H¹-NMR was consistent with the structure.

Example 2.68b:5-cyclohexyl-1-ethyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

To a suspension of5-cyclohexyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.47c) (500 mg, 1.65 mmol) and NaH (80 mg, 1.98 mmol) in 10 mLDMF was added ethyl bromide (147 uL, 1.98 mmol). The reaction wasstirred for 18 h at ambient temperature. Additional NaH and ethylbromide were added. The resulting mixture was stirring 3 more hours,then the mixture was treated with EtOAc and H₂O. The organic layer wasdried and concentrated to give a yellow oil. The crude product waspurified by flash chromatography using a 12 g Silicycle column andEtOAc/Hex gradient as eluant to obtain the pure product (352 mg, 64%) asa light yellow oil. MS 345 (MH⁺). H¹-NMR was consistent with thestructure.

Example 2.69:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60 starting from5-(cyclohex-1-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.69a) (42 mg, 0.2 mmol) and 2-bromo-1-(1H-pyrrol-2-yl)ethanone (45 mg,0.22 mmol) to obtain the desired product (12 mg, 20%) as a white solid.¹H NMR is consistent with structure. MS 316 (MH⁺).

Example 2.69a:5-(cyclohex-1-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60a starting from5-(cyclohex-1-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.69b) (328 mg, 1 mmol) to obtain the desired product (104 mg,50%) as a white solid. ¹H NMR is consistent with structure. MS 329(MH⁺).

Example 2.69b:5-(cyclohex-1-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60b starting from5-(cyclohex-1-en-1-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione (69c)(600 mg, 2 mmol) to obtain the product (540 mg, 82%) as a white solid.¹H NMR is consistent with structure. MS 329 (MH⁺).

Example 2.69c:5-(cyclohex-1-en-1-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60c starting from5-(cyclohex-1-en-1-yl)imidazolidine-2,4-dione (Example 2.69d) (720 mg, 4mmol) to obtain the desired product (900 mg, 75%) as a white solid. ¹HNMR is consistent with structure. MS 301 (MH⁺).

Example 2.69d: 5-(cyclohex-1-en-1-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting fromcyclohex-1-enecarbaldehyde (1100 mg, 10 mmol) to obtain the desiredproduct (800 mg, 44%) as a white solid. ¹H NMR is consistent withstructure. MS 181 (MH⁺).

Example 2.70:5-(2-methoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (3.0 mL),5-(2-methoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.70a) (170 mg, 0.5 mmol), K₂CO₃ (138.0 mg, 1 mmol), and MeI(38 uL, 1.2 mmol). The reaction medium was stirred vigorously at roomtemperature for 21 hours, poured in water (20 mL) and extracted withEtOAc (3×). Combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified bypreparative HPLC using a CH₃CN/H₂O gradient as eluant to obtain the puredesired product (76 mg, 43%) as an oily film. ¹H NMR (400 MHz, DMSO-d₆)δ 8.11-8.05 (m, 2H), 7.71 (t, J=7.4 Hz, 1H), 7.57 (dd, J=11.6, 4.3 Hz,2H), 7.50 (dd, J=8.0, 1.6 Hz, 1H), 7.45-7.37 (m, 1H), 7.08-6.99 (m, 2H),5.05 (s, 2H), 3.72 (s, 3H), 3.31 (s, 3H), 1.77 (s, 3H). MS 353 (MH⁺).

Example 2.70a:5-(2-methoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (4.0 mL),5-(2-methoxyphenyl)-5-methylimidazolidine-2,4-dione (Example 2.60d) (220mg, 1.0 mmol), K₂CO₃ (276 mg, 2.0 mmol), and 2-bromo-1-phenylethanone(199 mg, 1.0 mmol). The reaction medium was stirred vigorously at roomtemperature for 19 hours, poured in water (20 mL) and extracted withEtOAc (3×). Combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 40 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure desired product (300 mg, 89%) as awhite powder. ¹H NMR (400 MHz, CDCl₃) δ 8.02-7.95 (m, 2H), 7.66-7.60 (m,1H), 7.57 (dd, J=7.7, 1.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.34 (ddd, J=8.2,7.5, 1.7 Hz, 1H), 7.02-6.94 (m, 2H), 6.46 (s, 1H), 5.05-4.93 (m, 2H),3.92 (s, 3H), 1.90 (d, J=6.6 Hz, 3H). MS 339 (MH⁺).

Example 2.71:5-(2-hydroxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous methanol (5.0 mL),5-(2-benzyloxy)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.120) (86 mg, 0.2 mmol), 10% Pd/C (25 mg), and the reactionmedium was stirred vigorously and hydrogenated with hydrogen balloon atroom temperature overnight. The reaction mixture was filtered throughplug of Celite and the solvent was evaporated. The residue was purifiedby HPLC to obtain the pure product (20 mg, 30%) as a white powder. ¹HNMR (400 MHz, CDCL₃) δ 8.00-7.93 (m, 2H), 7.66-7.58 (m, 1H), 7.54-7.45(m, 2H), 7.32-7.19 (m, 2H), 6.98 (td, J=7.7, 1.2 Hz, 1H), 6.90 (dd,J=8.0, 1.1 Hz, 1H), 4.99 (s, 2H), 2.85 (s, 3H), 1.98 (s, 3H).

Example 2.72:5-cyclohexyl-3-(2-(4-fluorophenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (210mg, 1 mmol) and 2-bromo-1-(3-fluorophenyl)ethanone (260 mg, 1.2 mmol) toobtain the desired product (280 mg, 81%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ 8.11 (dd, J=5.6 Hz, J=8.8 Hz, 2H), 7.39 (t, J=8 Hz, 2H),4.94 (s, 2H), 2.79 (s, 3H), 1.73-1.67 (m, 4H), 1.61-1.58 (m, 2H), 1.36(s, 3H), 1.34-1.30 (m, 1H), 1.21-1.13 (m, 2H), 1.04-1.00 (m, 1H),0.92-0.88 (m, 1H).

Example 2.73:5-(cyclohex-1-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60 starting from5-(cyclohex-1-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.69a) (52 mg, 0.25 mmol) and 2-bromo-1-(pyridin-3-yl)ethanonehydrochloride (84 mg, 0.3 mmol) to obtain the product (35 mg, 43%) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.23-9.15 (m, 1H), 8.84(dd, J=4.8, 1.7 Hz, 1H), 8.28-8.17 (m, 1H), 7.47 (ddd, J=8.0, 4.8, 0.8Hz, 1H), 5.98-5.92 (m, 1H), 4.94 (s, 2H), 2.81 (s, 3H), 2.15 (dd, J=7.6,5.1 Hz, 2H), 1.91 (d, J=4.2 Hz, 2H), 1.77-1.53 (m, 7H). MS 328 (MH⁺).

Example 2.74:5-(2-ethoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(2-ethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.74a) (319 mg, 0.9 mmol) and methyl iodide (67 uL, 1.08 mmol)to obtain product as a white powder (81 mg, 25% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.08 (d, J=8 Hz, 2H), 7.71 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz,2H), 7.49 (d, J=8 Hz, 1H), 7.38 (t, J=8 Hz, 1H), 5.01 (q, J=16 Hz, J=56Hz, 2H),3.945 (q, J=8 Hz, J=12 Hz, 2H), 2.48 (s, 3H), 1.78 (s, 3H), 1.22(t, J=8 Hz, 3H). MS 367 (MH⁺).

Example 2.74a:5-(2-ethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(2-ethoxyphenyl)-5-methylimidazolidine-2,4-dione (Example 2.74b) (234mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol) to obtain productas a white powder (320 mg, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.38(s, 1H), 8.07 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz,2H), 7.44 (d, J=8 Hz, 1H), 7.33 (t, J=8 Hz, 1H), 6.96 (m, 2H), 4.95 (q,J=18 Hz, J=40 Hz, 2H), 3.95 (q, J=8 Hz, J=12 Hz, 2H), 3.31 (s, 3H), 1.75(s, 3H), 1.25 (t, J=8 Hz, 3H). MS 352 (MH⁺).

Example 2.74b: 5-(2-ethoxyphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2-ethoxy phenyl)ethanone (984 mg, 6 mmol) to obtain product as awhite powder (1.3 g, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s,1H), 7.87 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.30 (t, J=8 Hz, 1H), 6.96 (m,2H), 3.95 (m, 2H), 1.61 (s, 3H), 1.26 (t, J=8 Hz, 3H). MS 235 (MH⁺).

Example 2.75:5-((1R,4S)-bicyclo[2.2.1]heptan-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

The title compound was isolated during the purification of 42. Compound75 eluted after compound 42 on the HPLC during the separation of thediastereomers. The procedure is identical to that of 42. ¹H-NMR (400MHz, DMSO-d₆) δ 8.05-8.03 (s, 2H), 7.73-7.69 (m, 1H), 7.59-7.56 (m, 2H),4.97 (s, 2H), 2.83 (s, 3H), 2.21 (s, 1H), 2.02 (s, 1H), 1.89-1.86 (m,2H), 2.02 (s, 1H), 1.89-1.86 (m, 2H), 1.49-1.47 (m, 2H), 1.35-1.29 (m,4H), 1.19-1.14 (m, 3H), 0.97-0.95 (m, 1H); MS 341 (MH⁺).

Example 2.76:5-(2-isopropoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(2-isopropoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.76a) (183 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 53%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (dd, J=8.4, 1.3 Hz, 2H), 7.61 (d, J=7.4 Hz, 1H), 7.55-7.47(m, 2H), 7.45 (dd, J=7.8, 1.6 Hz, 1H), 7.38-7.30 (m, 1H), 6.98 (td,J=7.6, 1.1 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 4.99 (d, J=2.1 Hz, 2H),4.67-4.57 (m, 1H), 2.62 (s, 3H), 1.93 (s, 3H), 1.27 (dd, J=13.3, 6.0 Hz,6H). MS 381 (MH⁺).

Example 2.76a:5-(2-isopropoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-(2-isopropoxyphenyl)-5-methylimidazolidine-2,4-dione (Example 2.76b)(264 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1.0 mmol) toobtain the desired product (283 mg, 77%) as a white solid. ¹H NMR isconsistent with structure. MS 367 (MH⁺).

Example 2.76b: 5-(2-isopropoxyphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(2-isopropoxyphenyl)ethanone (1424 mg, 8 mmol) to obtain the desiredproduct (1.7 g, 86%) as a white solid. ¹H NMR is consistent withstructure. MS 249 (MH⁺).

Example 2.77:5-cycloheptyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-cycloheptyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.77a) (50 mg, 0.15 mmol) and MeI (12 uL, 0.2 mmol) to obtainthe desired product (20 mg, 39%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.02-7.93 (m, 2H), 7.66-7.58 (m, 1H), 7.49 (ddd, J=6.7, 4.6,1.1 Hz, 2H), 4.91 (s, 2H), 2.91 (s, 3H), 1.91-1.63 (m, 6H), 1.62 (s,1H), 1.61-1.53 (m, 3H), 1.53-1.50 (m, 4H), 1.41-1.25 (m, 2H). MS 343(MH⁺).

Example 2.77a:5-cycloheptyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-cycloheptyl-5-methylimidazolidine-2,4-dione (Example 2.77b) (105 mg,0.5 mmol) and 2-bromo-1-phenylethanone (100 mg, 0.5 mmol) to obtain thedesired product (80 mg, 49%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.02-7.92 (m, 2H), 7.67-7.58 (m, 1H), 7.50 (ddd, J=8.0, 6.8, 1.1 Hz,2H), 5.49 (s, 1H), 4.91 (s, 2H), 1.98-1.88 (m, 2H), 1.81-1.65 (m, 3H),1.62-1.55 (m, 3H), 1.52 (d, J=4.6 Hz, 3H), 1.51-1.36 (m, 4H), 1.29-1.17(m, 1H). MS 329 (MH⁺).

Example 2.77b: 5-cycloheptyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-cycloheptyl-ethanone (600 mg, 4.28 mmol) to obtain the desired product(250 mg, 28%) as a white solid. ¹H NMR is consistent with structure. MS211 (MH⁺).

Example 2.78:3-(2-(4-aminophenyl)-2-oxoethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

To a solution of5-cyclohexyl-1,5-dimethyl-3-(2-(4-nitrophenyl)-2-oxoethyl)imidazolidine-2,4-dione (Example 2.78a) (240 mg, 0.64 mmol) in MeOH (5mL) was added Pd/C (10%, 48 mg) under N₂. The resulting mixture wasstirring at room temperature for 2 hrs. The mixture was filtered throughcelite and concentrated and the resulting crude material was purified bymass-triggered HPLC. The desired product (120 mg, 54%) was obtained as aclear colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (d, J=8.8 Hz, 2H),6.55 (d, J=8.8 Hz, 2H), 6.20 (s, 2H), 4.69 (s, 2H), 2.78 (s, 3H),1.56-1.73 (m, 6H), 0.91-1.29 (m&s, 8H). MS 344 (MH⁺).

Example 2.78a:5-cyclohexyl-1,5-dimethyl-3-(2-(4-nitrophenyl)-2-oxoethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL), 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.47a) (210 mg, 1.0 mmol), and the solution was cooled to 0° C.in an ice bath. NaH (48 mg, 1.2 mmol), and2-bromo-1-(4-nitrophenyl)ethanone (293 mg, 1.2 mmol) was added the icebath was removed and the reaction medium was stirred vigorously at roomtemperature for 1.5 hr. The mixture was diluted with water and extractedwith EtOAc (3×10 mL). The combined organic phases were washed with brineand dried over MgSO₄, and solvents were evaporated. The residue waspurified by flash chromatography using a 12 g Silicycle column andEtOAc/Hex gradient as eluant to obtain the pure product (300 mg, 80%) asa light yellow oil. MS 374 (MH⁺). H¹-NMR is consistent with thestructure.

Example 2.79:5-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(6,6-dimethybicyclo[3.1.1]hept-2-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.79a) (24.5 mg, 0.1 mmol) and 2-bromoacetophenone (24 mg, 0.12mmol). Gives 3.1 mg (8% yield) of product as a white powder. On HPLCthis isomer elutes first. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J=8 Hz,2H), 7.61 (t, J=8 Hz, 1H), 7.49 (t, J=8 Hz, 2H), 5.79 (m, 1H), 4.92 (s,2H), 2.82 (s, 3H), 2.29-2.44 (m, 3H), 2.17 (t, J=4 Hz, 1H), 2.10 (m,1H), 1.63 (s, 3H), 1.29 (s, 3H), 1.14 (d, J=8 Hz, 1H), 0.84 (s, 3H). MS367 (MH⁺).

Example 2.79a:5-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.79b) (470 mg, 1.27 mmol) and a solution of ammonium ceriumnitrate (1.82 g, 3.32 mmol) in water (10 mL) to obtain product as awhite powder of mixture of 2 pairs of diastereomers (24.5 mg, 8% yield).¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (bs, 1H), 5.69 (m, 1H), 2.56-2.57 (2s,3H), 2.20-2.38 (m, 3H), 2.04 (m, 1H), 1.67-1.77 (m, 1H), 1.38-1.39 (2s,3H), 1.19-1.21 (2s, 3H), 0.98 (m, 1H), 0.68-0.75 (2s, 3H). MS 249 (MH⁺).

Example 2.79b:5-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione(Example 2.79c) (552 mg, 1.62 mmol) and methyl iodide (222 uL, 3.56mmol) to obtain product as a colorless oil of mixture of 2 pairs ofdiastereomers 2:1 ratio (471.3 mg, 79% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 7.16 (d, J=8 Hz, 1.3H), 7.13 (d, J=8 Hz, 0.7H), 6.85 (d, J=8 Hz, 2H),5.70 (dm, J=12 Hz, 1H), 4.44 (m, 2H), 3.69-3.70 (2s, 3H), 2.61-2.63 (2s,3H), 2.16-2.30 (m, 3H), 1.98 (m, 1H), 1.60 (t, J=4 Hz, 0.3H), 1.45 (t,J=4 Hz, 0.7H), 1.41 (s, 3H), 1.14 (s, 1H), 0.96 (s, 2H), 0.92 (m, 1H),0.69 (s, 1H), 0.55 (s, 2H). MS 369 (MH⁺).

Example 2.79c:5-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-3-(4-methoxybenzyl)-imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45c starting from5-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)imidazolidine-2,4-dione(Example 2.79d) (1.21 g, 5.5 mmol) and 4-methoxybenzyl chloride (896 uL,6.6 mmol) to obtain product as a yellowish powder (552.4 mg, 30% yield).¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.16 (d, J=8 Hz, 2H), 6.85 (d,J=8 Hz, 2H), 4.45 (s, 2H), 3.94 (t, J=4 Hz, 1H), 3.69 (s, 3H), 2.32-2.40(m, 3H), 1.85-1.97 (m, 3H), 1.30 (d, J=8 Hz, 1H), 1.23 (s, 3H), 0.65 (s,3H). MS 341 (MH⁺).

Example 2.79d:5-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from(1R)-(−)-myrtenal (1.5 g, 10 mmol) to obtain product as a white powder(1.87 g, 85% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 9.63 (s,1H), 3.90 (t, J=4 Hz, 1H), 2.31-2.37 (m, 3H), 1.85-1.97 (m, 3H), 2.30(d, J=8 Hz, 1H), 1.21 (s, 3H), 0.65 (s, 3H). MS 221 (MH⁺).

Example 2.80:1,5-dimethyl-5-(3-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-methyl-5-(3-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.80a) (534 mg, 1.63 mmol) and methyl iodide (122 uL, 1.95mmol) to obtain product as a white powder of mixture of 4 pairs ofdiastereomers (236 mg, 42% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d,J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.94 (s, 2H),2.80 (t, J=8 Hz, 3H), 1.86-2.08 (m, 1H), 1.39-1.80 (m, 5H), 1.35-1.38(2s, 3H), 1.15-1.40 (m, 3H), 0.87-1.03 (m, 1H), 0.95 (dd, J=2.8 Hz,J=7.4 Hz, 1H), 0.86 (t, J=8 Hz, 2H), 0.57-0.74 (m, 1H). MS 329 (MH⁺).

Example 2.80a:5-methyl-5-(3-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-methyl-5-(3-methylcyclohexyl)imidazolidine-2,4-dione (Example 2.80b)(420 mg, 2 mmol) and 2-bromoacetophenone (478 mg, 2.4 mmol) to obtainproduct as a white powder of mixture of 4 pairs of diastereomers (540mg, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=8 Hz, 1H), 8.02(d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.90 (s,2H), 1.96-2.05 (m, 0.5H), 1.41-1.77 (m, 5H), 1.17-1.36 (m, 2.5H),1.28-1.31 (4s, 3H), 0.97 (m, 1H), 0.83-0.94 (4d, J=6 Hz, 3H), 0.73 (m,1H). MS 329 (MH⁺).

Example 2.80b: 5-methyl-5-(3-methylcyclohexyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(3-methylcyclohexyl)-ethanone (Example 2.80c) (2.72 g, 19.44 mmol) toobtain product as a white powder of mixture of 4 pairs of diastereomers(2.52 g, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (bs, 1H), 7.78(s, 1H), 1.96-2.05 (m, 0.5H), 1.63-1.72 (m, 1.5H), 1.57 (m, 1H), 1.48(m, 1H), 1.22-1.38 (m, 3H), 1.14-1.18 (4s, 3H), 0.14-1.22 (m, 1H),0.80-0.92 (4d, J=6 Hz, 3H), 0.60-0.73 (m, 1H). MS 211 (MH⁺).

Example 2.80c: 1-(3-methylcyclohexyl)-ethanone

Prepared in a similar manner as described in Example 2.59e starting from3-methylcyclohexane-carboxylic acid (2.87 mL, 20 mmol) to obtain productas a colorless oil consisting of two pairs of diastereomers (2:1 ratioby NMR analysis) (2.72 g, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.53 (m,0.3H), 2.30 (m, 0.7H), 2.07 (2s, 3H), 1.72-1.83 (m, 3H), 1.59-1.64 (m,1H), 1.49 (m, 1H), 1.36 (m, 1H), 1.15-1.26 (m, 1H), 0.96-1.12 (m, 1H0,0.85-0.86 (2s, 3H), 0.76-0.83 (m, 1H). MS N/A (MH⁺).

Example 2.81:5-cyclohexyl-3-(2-(3,4-dihydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (100.0mg, 476 umol), and commercially available2-chloro-1-(3,4-dihydroxyphenyl)ethanone (100.0 mg, 536 umol), to obtainthe desired product (47.6 mg, 28%). ¹H NMR (400 MHz, d₆-DMSO) δ 7.45(dd, J=8.3, 2.2 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H),4.78 (s, 2H), 2.81 (s, 3H), 1.78-1.66 (m, 4H), 1.65-1.57 (m, 2H), 1.37(s, 3H), 1.36-1.28 (m, 1H), 1.26-1.12 (m, 2H), 1.10-0.91 (m, 2H). MS 361(MH⁺).

Example 2.82:3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (100.0mg, 476 umol), and commercially available1-(benzo[d][1,3]dioxol-5-yl)-2-bromoethanone (144.0 mg, 592 umol), toobtain the desired product. ¹H NMR (400 MHz, d₆-DMSO) δ 7.70 (dd, J=8.2,1.8 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.17 (s,2H), 4.87 (s, 2H), 2.81 (s, 3H), 1.79-1.66 (m, 4H), 1.65-1.56 (m, 2H),1.38 (s, 3H), 1.37-1.28 (m, 1H), 1.25-1.12 (m, 2H), 1.10-1.00 (m, 1H),0.99-0.87 (m, 1H). MS 374 (MH⁺).

Example 2.83:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-4-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (68 mg, 0.32 mmol)(Example 2.47a) and 4-(bromoacetyl)-pyridine hydrobromide (108 mg, 0.38mmol) to obtain the desired product (30 mg, 23%) as a light yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (d, J=4.4 Hz, 2H), 7.73 (d, J=4.4 Hz,2H), 4.88 (s, 2H), 2.91 (s, 3H), 1.665 (m, 6H), 1.47 (s & m, 4H), 1.01(m, 4H). MS 330 (MH⁺).

Example 2.84:1,5-dimethyl-5-(4-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from1,5-dimethyl-5-(4-methylcyclohexyl)-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.84a) (386 mg, 1 mmol) to obtain product as a colorless oilyfilm consisting of two pairs of diastereomers (2:1 ratio by NMRanalysis) (20 mg, 6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (d, J=8Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.94 (m, 2H), 2.80(s, 2H), 2.79 (s, 1H), 1.88 (m, 1H), 1.52-1.71 (m, 3H), 1.30-1.48 (m,4H), 1.37 (s, 3H), 1.16 (m, 1H), 0.87-1.05 (m, 1H), 0.83 (m, 3H). MS 343(MH⁺).

Example 2.84a:1,5-dimethyl-5-(4-methylcyclohexyl)-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)-imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.95b starting from5-(4-methylcyclohexyl)-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.84b) (395 mg, 1.1 mmol) to obtain product as a colorless oilconsisting of two pairs of diastereomers (386 mg, 90% yield). MS 387(MH⁺).

Example 2.84b:5-(4-methylcyclohexyl)-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.95c starting frommethyl2-(4-methyl-cyclohexyl)-2-(3-((2-phenyl-1,3-dioxolan-2-yl)methyl)ureido)acetate(Example 2.84c) (460 mg, 1.18 mmol) to obtain product as a white solid(398.6 mg, 94% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.37 (m, 5H),3.89 (m, 2H), 3.67 (m, 4H), 1.88 (m, 1H), 1.52-1.71 (m, 3H), 1.30-1.48(m, 4H), 1.16 (m, 1H), 0.87-1.05 (m, 1H), 0.85 (m, 3H). MS 359 (MH⁺).

Example 2.84c: Methyl2-(4-methylcyclohexyl)-2-(3-((2-phenyl-1,3-dioxolan-2-yl)methyl)ureido)acetate

Prepared in a similar manner as described in Example 2.95d starting frommethyl 2-amino-2-(4-methylcyclohexyl)acetate (Example 2.84d) (225 mg,1.21 mmol) and 2-(isocyanatomethyl)-2-phenyl-1,3-dioxolane (373 mg, 1.82mmol) to obtain product as a colorless oil (461.6 mg, 98% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 7.27-7.39 (m, 5H), 6.38 (d, J=8 Hz, 1H), 6.03 (q,J=6 Hz, J=12 Hz, 1H), 4.11 (t, J=8 Hz, 0.5H), 4.01 (m, 2.5H), 3.73 (m,2H), 3.58 (s, 3H), 3.40 (m, 1H), 3.30 (m, 1H), 1.63 (m, 2H), 1.34-1.49(m, 3H), 1.13-1.30 (m, 3H), 0.98 (m, 1H), 0.85 (m, 1H), 0.88 (d, J=8 Hz,1.5H), 0.82 (d, J=8 Hz, 1.5H). MS 391 (MH⁺).

Example 2.84d: Methyl 2-amino-2-(4-methylcyclohexyl)acetate

Prepared following Scheme A.

Example 2.84d-1: Methyl 2-amino-2-(4-methylcyclohexyl)acetate

2-Amino-2-(4-methylcyclohexyl)acetonitrile hydrochloride (Example2.84d-2) (335 mg, 1.77 mmol) in 200 mL of MeOH was saturated with HClgas and then heated at 90° C. for 18 h. Reaction mixture wasconcentrated in vacuum; residue was washed with saturated NaHCO₃ andproduct was extracted with EtOAc (3×20 mL). Combined organic fractionswere washed with brine, dried over MgSO₄ and solvent was removed invacuum to obtain product as a colorless oil (227 mg, 69% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 3.58 (s, 3H), 3.12 (dd, J=6 Hz, J=40 Hz, 1H), 1.65(m, 2H), 1.34-1.49 (m, 3H), 1.13-1.30 (m, 3H), 0.98 (m, 1H), 0.85 (m,1H), 0.87 (d, J=8 Hz, 1.5H), 0.82 (d, J=8 Hz, 1.5H). MS 186 (MH⁺).

Example 2.84d-2: 2-amino-2-(4-methylcyclohexyl)acetonitrilehydrochloride

N-(cyano(4-methylcyclohexyl)methyl)-4-methylbenzenesulfinamide (Example2.84d-3) (730.7 mg, 2.52 mmol) in 35 mL MeOH was heated at 110° C. for18 h with 4N HCl in dioxane (36.5 mL, 146 mmol). Then reaction mixturewas concentrated in vacuum, residue was diluted with water (20 mL) andsaturated NaHCO₃ (10 mL) and then extracted with EtOAc (3×20 mL).Combined organic fractions were washed with brine, dried over MgSO₄ andsolvent was removed in vacuum. To the residue was added 10 mL of 4N HClin dioxane and reaction mixture was concentrated in vacuum again.Obtained product was washed with ether, filtered off and dried in vacuumto give 335 mg of product as a white powder (79% yield). ¹H NMR (400MHz, D₂O) δ 4.30 (dd, J=6 Hz, J=32 Hz, 1H), 1.90 (m, 0.5H), 1.73-1.85(m, 1H), 1.62-1.70 (m, 2.5H), 1.07-1.54 (m, 5H), 0.86 (m, 1H), 0.79 (d,J=8 Hz, 1.5H), 0.73 (d, J=8 Hz, 1.5H). MS 153 (MH⁺).

Example 2.84d-3:N-(cyano(4-methylcyclohexyl)methyl)-4-methylbenzenesulfinamide

To a solution of diethylaluminum cyanide (1M in Toluene, 11.4 mL, 11.4mmol) in 10 mL of anhydrous THF at −78° C. under N₂ atmosphere was addedisopropanol (4.56 mL, 7.6 mmol), warmed up to room temperature andstirred 30 min. Obtained solution was cannulated to the solution of(E)-4-methyl-N-((4-methylcyclohexyl)methylene)benzenesulfinamide(Example 2.84d-4) (2 g, 7.6 mmol) in 40 mL of anhydrous THF cooled to−78° C. under N₂ atmosphere. Then reaction mixture was gradually warmedup to room temperature and stirred for 18 h. Obtained yellow solutionwas cooled to −78° C. and saturated NH₄Cl (50 mL) was added dropwise.Reaction mixture was warmed up to room temperature, and then filteredtrough Celite. Filtrate was extracted with EtOAc (3×20 mL). Combinedorganic fractions were washed with brine, dried over MgSO₄ and solventwas removed in vacuum. Crude product was purified by flashchromatography using a 80 g Silicycle column (Hexane/EtOAc 20% gradient;R_(f)=0.3) to give 730.7 mg (33% yield) of product as a yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 7.51 (d, J=8 Hz, 2H), 7.43 (t, J=8 Hz, 1H),7.38 (d, J=8 Hz, 2H), 4.10 (dt, J=8 Hz, J=48 Hz, 1H), 2.36 (s, 3H), 1.79(m, 1H), 1.67 (m, 2H), 1.38-1.59 (m, 4H), 1.23-1.33 (m, 2H), 0.96-1.09(m, 1H), 0.87 (d, J=8 Hz, 1.5H), 0.83 (d, J=8 Hz, 1.5H). MS 291 (MH⁺).

Example 2.84d-4:(E)-4-Methyl-N-((4-methylcyclohexyl)methylene)benzenesulfinamide

To the solution of 4-methylcyclohexanecarbaldehyde (Example 2.84d-5)(4.37 g, 34.68 mmol), (S)-(+)-p-Toluenesulfinamide (3.58 g, 23 mol) in50 mL of anhydrous DCM was added Titanium (IV) ethoxide (14.46 mL, 69mmol) and reaction mixture was heated at 40° C. for 18 h. Reactionmixture was diluted with water (40 mL) and 100 mL of DCM was added andresulting mixture was filtered trough Celite. Filtrate was extractedwith DCM, combined organic phases were washed with H₂O and brine, driedover MgSO₄ and solvent was removed in vacuum. Crude product was purifiedby flash chromatography using a 120 g Silicycle column (Hexane/EtOAc 20%gradient; R_(f)=0.6) to give 5.83 g (64% yield) of(E)-4-methyl-N-((4-methylcyclohexyl)-methylene)benzenesulfinamide as afluorescented yellow oil. MS 264 (MH⁺).

Example 2.84d-5: 4-Methylcyclohexanecarbaldehyde

To a solution of (4-methylcyclohexyl)methanol (Example 2.84d-6) (4.83 g,37.7 mmol) in 200 mL of anhydrous DCM was added Dess-Martin periodinane(24 g, 56.6 mol) and reaction mixture was stirred at room temperaturefor 2.5 h. Then reaction mixture was diluted with 1N NaOH and washedwith it until all precipitate dissolved (˜600 mL). Basic solution wasextracted with DCM, combined organic fractions were washed with brine,dried over MgSO₄ and concentrated in vacuum. To the residue was added 50mL of ether, formed precipitate was filtered off and filtrate wasconcentrated in vacuum to give a product as colorless oil, which wasused in to next step without purification (5.74 g, 100% yield). ¹H NMR(400 MHz, CDCl₃) δ 9.64 (s, 1H), 2.32 (m, 1H), 1.87-2.03 (m, 2H), 1.75(m, 1H), 1.49-1.53 (m, 4H), 1.39 (m, 1H), 0.84 (m, 1H), 0.85 (d, J=8 Hz,1H), 0.81 (d, J=8 Hz, 2H). MS N/A (MH⁺).

Example 2.84d-6: (4-Methylcyclohexyl)methanol

To a solution of 4-methylcyclohexanecarboxylic acid (5 g, 35.21 mmol,mix of cis- and trans-isomers) in 20 mL of anhydrous THF at −20° C.under N₂ atmosphere was added portionwise LiAlH₄ (95% powder, 1.4 g,35.2 mmol). Reaction mixture was gradually warmed up to room temperatureand stirred for 18 h. Then cooled to −20° C. and added H₂O (1.4 mL),then 15% NaOH (1.4 mL), and then H₂O (4 mL). Reaction mixture wasallowed to stir at room temperature another 30 min, then anhydrousNa₂SO₄ was added (˜10 g) and reaction mixture was diluted with ether (50mL) and filtered. Filtrate was concentrated in vacuum to obtain crudeproduct as colorless oil mixture of 2 pair of diastereomers 2:1 ratio90% clean by LCMS analysis (4.83 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ3.74 (m, 0.5H), 3.53 (d, J=8 Hz, 1.4H), 3.44 (d, J=8 Hz, 0.6H), 1.85 (m,0.5H), 1.61-1.76 (m, 3H), 1.40-1.53 (m, 4H), 1.22-1.28 (m, 2H), 0.92 (m,1H), 0.91 (d, J=8 Hz, 2H), 0.88 (d, J=8 Hz, 1H). MS N/A (MH⁺).

Example 2.85:1,5-dimethyl-3-(2-oxo-2-phenylethyl)-5-(pentan-3-yl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (20 mL),5-methyl-3-(2-oxo-2-phenylethyl)-5-(pentan-3-yl)imidazolidine-2,4-dione(Example 2.85a) (778 mg, 2.57 mmol), K₂CO₃ (532 mg, 3.85 mmol), and MeI(546 mg, 3.85 mmol). The reaction medium was stirred vigorously at roomtemperature for 21 hours, diluted with water and extracted with EtOAc(3×20 mL). The combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 12 g Silicycle column and a Hexanes/EtOAcgradient as eluant to obtain the pure product (750 mg, 86%) as an oilyfilm. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.4 Hz, 2H), 7.47 (t, J=7.2Hz, 1H), 7.26 (t, J=7.2 Hz, 2H), 4.92 (s, 2H), 2.91 (s, 3H), 1.72 (m,1H), 1.25˜1.57 (s&m, 7H), 0.95 (t&t, J=7.6 Hz, 7.6 Hz, 6H). MS 317(MH⁺).

Example 2.85a:5-methyl-3-(2-oxo-2-phenylethyl)-5-(pentan-3-yl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8 mL), 5-methyl-5-(pentan-3-yl) imidazolidine-2,4-dione(Example 2.85b) (600 mg, 3.26 mmol), K₂CO₃ (675 mg, 4.89 mmol), and2-bromo-1-phenylethanone (973 mg, 4.89 mmol). The reaction mixture wasstirred vigorously at room temperature for 19 hours, diluted with waterand extracted with EtOAc (3×10 mL). The combined organic phases werewashed with brine and dried over MgSO₄, and solvents were evaporated.The residue was purified by flash chromatography using a 12 g Silicyclecolumn and a Hexanes/EtOAc gradient as eluant to obtain the pure product(778 mg, 52%) as a white powder. MS 303 (MH⁺). H¹-NMR is consistent withthe structure.

Example 2.85b: 5-methyl-5-(pentan-3-yl)imidazolidine-2,4-dione

In a N₂-flushed 150 mL pressure tube, were added H₂O (20 mL),3-ethylpentan-2-one (2.0 g, 17.5 mmol) in MeOH (20 mL), (NH₄)₂CO₃ (5.21g, 54.3 mmol), and KCN (1.25 g, 19.2 mmol) in H₂O (7 mL) was addeddropwise over a few minutes. The tube was sealed and heated at 50° C.for 48 hours. The reaction medium was allowed to cool to roomtemperature and the obtained white precipitate was filtered and washedwith cold H₂O, then dried to obtain the pure product (3.3 g, 93%). MS185 (MH⁺). H¹-NMR is consistent with the structure.

Example 2.86:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (68 mg, 0.32 mmol)(Example 2.47a) and 2-bromo-acetylthiophenone (79 mg, 0.38 mmol) toobtain the desired product (6 mg, 6%) as a light yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 7.788 (d, J=4 Hz, 1H), 7.699 (d, J=4.4 Hz), 7.161 (dd,J=4.4 Hz & 4 Hz) 4.847 (S, 2H), 2.906 (s, 3H), 1.659 (m, 6H), 1.471 (s,3H), 1.037 (m, 5H). MS 335 (MH⁺).

Example 2.87:5-cyclohexyl-1,5-dimethyl-3-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (0.109g, 0.520 mmol), K₂CO₃ (0.086 g, 0.62 mmol), and2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethanone (0.126 g, 0.62 mmol) in 0.5mL DMF. The title compound was obtained as white solid 70 mg (41%).¹H-NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.04 (s, 1H), 4.64 (s, 2H),3.90 (s, 3H), 2.80 (s, 3H), 1.76-1.57 (m, 6H), 1.39-1.28 (m, 4H),1.23-0.90 (m, 4H); MS 333 (MH⁺).

Example 2.88:5-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(bicyclo[2.2.1]hept-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.88a) (162 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (eluted second on HPLC) (50 mg, 39%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.93 (m, 2H), 7.64-7.58 (m, 1H),7.53-7.45 (m, 2H), 6.12 (dd, J=5.7, 3.1 Hz, 1H), 5.87 (dd, J=5.7, 2.9Hz, 1H), 4.87 (q, J=17.4 Hz, 2H), 2.99 (s, 3H), 2.87 (s, 1H), 2.80 (s,1H), 2.60-2.52 (m, 1H), 1.83 (dd, J=9.5, 3.8 Hz, 1H), 1.78-1.70 (m, 1H),1.49-1.40 (m, 4H), 1.29 (d, J=8.3 Hz, 1H). MS 339 (MH⁺).

Example 2.88a:5-(bicyclo[2.2.1]hept-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-(bicyclo[2.2.1]hept-5-en-2-yl)-5-methylimidazolidine-2,4-dione(Example 2.88b) (248 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1mmol) to obtain the desired product (250 mg, 77%) as a white solid(mixture of 2 isomers). First isomer: ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d,J=1.2 Hz, 1H), 7.98-7.93 (m, 2H), 7.64-7.58 (m, 1H), 7.53-7.45 (m, 2H),6.12 (dd, J=5.7, 3.1 Hz, 1H), 5.87 (dd, J=5.7, 2.9 Hz, 1H), 4.87 (q,J=17.4 Hz, 2H), 2.99 (s, 3H), 2.87 (s, 1H), 2.80 (s, 1H), 2.60-2.52 (m,1H), 1.83 (dd, J=9.5, 3.8 Hz, 1H), 1.78-1.70 (m, 1H), 1.49-1.40 (m, 3H),1.29 (d, J=8.3 Hz, 1H).

Second isomer: ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.90 (m, 2H), 7.66-7.58(m, 1H), 7.49 (tt, J=6.7, 1.1 Hz, 2H), 6.32 (dd, J=5.7, 3.1 Hz, 1H),6.01 (dd, J=5.7, 2.8 Hz, 1H), 5.19 (s, 1H), 4.88 (d, J=1.5 Hz, 2H), 3.10(s, 1H), 2.92 (s, 1H), 2.76-2.67 (m, 1H), 1.86 (ddd, J=12.0, 9.2, 3.9Hz, 1H), 1.57 (s, 3H), 1.52-1.43 (m, 1H), 1.34 (d, J=8.4 Hz, 1H), 1.00(ddd, J=11.9, 4.9, 2.6 Hz, 1H). MS 325 (MH⁺).

Example 2.88b:5-(bicyclo[2.2.1]hept-5-en-2-yl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (1360 mg, 10 mmol) to obtainthe desired product (1.3 g, 63%) as a white solid. MS 207 (MH⁺).

Example 2.89:5-cyclopentyl-1-ethyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclopentyl-1-ethyl-5-methylimidazolidine-2,4-dione (Example 2.89a)(85 mg, 0.40 mmol), and 2-bromo-1-phenylethanone (96 mg, 0.48 mmol), toobtain the pure product as a clear oil (60 mg, 45%). ¹H NMR (400 MHz,CDCl₃) δ 7.99-7.92 (m, 2H), 7.64-7.56 (m, 1H), 7.52-7.44 (m, 2H), 4.91(s, 2H), 3.45 (dq, J=14.5, 7.2 Hz, 1H), 3.31 (dq, J=14.3, 7.2 Hz, 1H),2.28 (tt, J=9.9, 7.9 Hz, 1H), 2.00-1.88 (m, 1H), 1.77-1.51 (m, 9H),1.47-1.36 (m, 1H), 1.29 (t, J=7.2 Hz, 3H).

Example 2.89a: 5-cyclopentyl-1-ethyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-cyclopentyl-1-ethyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.89b) (0.075 g, 0.33 mmol), and a solution of ammonium ceriumnitrate (1.52 g, 2.77 mmol) in water (8 mL), to obtain the pure productas a light brown solid (180 mg, 81%). MS 211 (MH⁺).

Example 2.89b:5-cyclopentyl-1-ethyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-cyclopentyl-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.45c) (500 mg, 1.65 mmol), and ethyl bromide (147 ul, 1.98mmol), to obtain the pure desired product as a clear oil (352 mg, 64%).MS 331 (MH⁺).

Example 2.90:1,5-dimethyl-5-((1s,4s)-4-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from1,5-dimethyl-5-(4-methylcyclohexyl)-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.84a) (386 mg, 1 mmol) to obtain product as a colorless oilyfilm. On HPLC this isomer eluted first (42.5 mg, 12% yield). ¹H NMR (400MHz, DMSO-d₆) δ 8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8Hz, 2H), 4.95 (d, J=16 Hz, J=24 Hz, 2H), 2.79 (s, 3H), 1.88 (m, 1H),1.52-1.71 (m, 2H), 1.39-1.57 (m, 5H), 1.37 (s, 3H), 1.29-1.37 (m, 1H),1.14 (m, 1H). MS 343 (MH⁺).

Example 2.91:5-(2-methoxy-5-methylphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(2-methoxy-5-methylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.91a) (117 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 55%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.03-7.95 (m, 2H), 7.61 (t, J=7.4 Hz, 1H), 7.50 (t, J=7.7 Hz,2H), 7.22 (d, J=1.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.79 (d, J=8.3 Hz,1H), 5.10-4.95 (m, 2H), 3.75 (s, 3H), 2.64 (s, 3H), 2.33 (s, 3H), 1.90(s, 3H). MS 367 (MH⁺).

Example 2.91a:5-(2-methoxy-5-methylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-(2-methoxy-5-methylphenyl)-5-methylimidazolidine-2,4-dione (Example2.91b) (234 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1 mmol) toobtain the desired product (250 mg, 71%) as a white solid. ¹H NMR isconsistent with structure. MS 353 (MH⁺).

Example 2.91b:5-(2-methoxy-5-methylphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(2-methoxy-5-methylphenyl)ethanone (820 mg, 5 mmol) to obtain thedesired product (800 mg, 68%) as a white solid. ¹H NMR is consistentwith structure. MS 235 (MH⁺).

Example 2.92:1,5-dimethyl-5-(3-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-methyl-5-(3-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.92a) (209 mg, 0.67 mmol) and methyl iodide (50 uL, 0.80 mmol)to obtain product as a white powder of mixture of 2 pairs ofdiastereomers 2:1 ratio (72.4 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.95(s, 2H), 2.80-2.81 (2s, 3H), 2.38 (m, 1H), 1.89 (m, 2H), 1.70 (m, 2H),1.58 (m, 1H), 1.43 (m, 1H), 1.38 (d, J=4 Hz, 3H), 1.06 (m, 1H), 0.93 (d,J=8 Hz, 2H), 0.91 (d, J=8 Hz, 1H). MS 329 (MH⁺).

Example 2.92a:5-methyl-5-(3-methylcyclopentyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-methyl-5-(3-methyl-cyclopentyl)imidazolidine-2,4-dione (Example 2.92b)(196 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol) to obtainproduct as a white powder of mixture of 4 pairs of diastereomers (209mg, 67% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (bs, 1H), 8.02 (d, J=8Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.90 (d, J=2.8 Hz,2H), 2.25 (m, 1H), 1.84 (m, 2H), 1.70 (m, 2H), 1.58 (m, 1H), 1.45 (m,1H), 1.31 (d, J=4 Hz, 3H), 1.06 (m, 1H), 0.97 (d, J=8 Hz, 2H), 0.91 (d,J=8 Hz, 1H). MS 315 (MH⁺).

Example 2.92b: 5-methyl-5-(3-methylcyclopentyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(3-methyl-cyclopentyl)ethanone (Example 2.92c) (1.25 g, 9.92 mmol) toobtain product as a white powder of mixture of 2 pairs of diastereomers(375 mg, 19% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (bs, 1H), 7.95(s, 1H), 2.13 (m, 1H), 1.64-1.84 (m, 4H), 1.13-1.52 (m, 2H), 1.198 (d,J=4 Hz, 3H), 1.02 (m, 1H), 0.94 (d, J=8 Hz, 1.5H), 0.90 (d, J=8 Hz,1.5H). MS 197 (MH⁺).

Example 2.92c: 1-(3-methyl-cyclopentyl)ethanone

Prepared in a similar manner as described in Example 2.59e starting from3-methylcyclopentane-carboxylic acid (Example 2.92d) (1.62 g, 12.65mmol) to obtain product as a colorless oil, the mixture of 2 pairs ofdiastereomers (2:1 ratio by NMR analysis) (375 mg, 19% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 2.95 (m, 0.7H), 2.65 (m, 0.3H), 2.06 (s, 3H), 2.03(m, 1H), 1.62-1.96 (m, 5H), 1.52 (m, 1H), 1.14 (m, 1H), 0.90-0.94 (2d,J=8 Hz, 3H). MS N/A (MH⁺).

Example 2.92d: 3-methylcyclopentane-carboxylic acid

4-Methylcyclohexanone (5.6 g, 50 mmol) was added to a mixture of 30%H₂O₂ (5.1 mL, 50 mmol) and selenium (IV) dioxide (111 mg, 1 mmol) in 60mL anhydrous t-BuOH and reaction mixture was heated at 80° C. for 18 h.Small particles of selenium were filtered off, reaction mixture wasconcentrated in vacuum and residue was diluted with saturated K₂CO₃ (˜50mL) and extracted with ether (3×25 mL). Aqueous phase was acidified withconc. HCl to pH=2 and extracted with ether (3×25 mL). Solvent wasremoved in vacuo and residue was distilled at 143-145° C./30 Torr toobtain the product as a colorless oil, the mixture of 2 pairs ofdiastereomers (2:1 ratio by NMR analysis) (1 g, 15.6%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.90 (s, 1H), 2.64 (m, 1H), 1.80-1.97 (m, 2H), 1.65-7.78 (m,3H), 1.08-1.25 (m, 2H), 0.94 (d, J=8 Hz, 2H), 0.92 (d, J=8 Hz, 1H). MSN/A (MH⁺).

Example 2.93:5-(cyclohex-3-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60 starting from5-(cyclohex-3-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.93a) (52 mg, 0.25 mmol) and 2-bromo-1-phenylethanone (50 mg, 0.25mmol) to obtain the desired product (40 mg, 49%) as a white solid. ¹HNMR is consistent with structure. ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.89(m, 2H), 7.66-7.57 (m, 1H), 7.49 (ddd, J=8.4, 1.6, 0.5 Hz, 2H), 5.69 (s,2H), 4.92 (d, J=3.2 Hz, 2H), 2.98-2.87 (m, 3H), 2.53-2.36 (m, 1H),2.22-1.94 (m, 4H), 1.92-1.73 (m, 1H), 1.53 (d, J=6.6 Hz, 3H), 1.39-1.24(m, 1H). MS 327 (MH⁺).

Example 2.93a:5-(cyclohex-3-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60a starting from5-(cyclohex-3-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.93b) (328 mg, 1 mmol) to obtain the desired product (104 mg,50%) as a white solid. ¹H NMR is consistent with structure. MS 329(MH⁺).

Example 2.93b:5-(cyclohex-3-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60b starting from5-(cyclohex-3-en-1-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione(Example 2.93c) (600 mg, 2 mmol) to obtain the desired product (540 mg,82%) as a white solid. ¹H NMR is consistent with structure. MS 329(MH⁺).

Example 2.93c:5-(cyclohex-3-en-1-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60c starting from5-(cyclohex-3-en-1-yl)imidazolidine-2,4-dione (Example 2.93d) (720 mg, 4mmol) to obtain the desired product (900 mg, 75%) as a white solid. ¹HNMR is consistent with structure. MS 301 (MH⁺).

Example 2.93d: 5-(cyclohex-3-en-1-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting fromcyclohex-3-enecarbaldehyde (1100 mg, 10 mmol) to obtain the desiredproduct (800 mg, 44%) as a white solid. ¹H NMR is consistent withstructure. MS 181 (MH⁺).

Example 2.94:5-(cyclopentylmethyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from5-(cyclopentylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.94a) (60 mg, 0.16 mmol) to obtain product as a colorless oilyfilm (20 mg, 38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8 Hz,2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.97 (s, 2H), 2.80 (s,3H), 1.82 (m, 2H), 1.69 (m, 1H), 1.38-1.64 (m, 6H), 1.34 (s, 3H), 1.01(m, 2H). MS 329 (MH⁺).

Example 2.94a:5-(cyclopentylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105a startingfrom1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105b) (100 mg, 0.34 mmol) to obtain product as a colorlessoil (60 mg, 47% yield). MS 373 (MH⁺).

Example 2.95:5-(cyclohex-2-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)imidazolidine-2,4-dione

To a 20 mL scintillation vial was added5-(cyclohex-2-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.95a) (108 mg, 0.5 mmol) (Example 2.95a) in dry DMF (5 mL). Sodiumhydride (52 mg, 1.30 mmol) was added to the solution followed by2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (167 mg, 0.60 mmol). Thereaction mixture was stirred at room temperature for 24 hr thenpartitioned between DCM (10 mL) and water (10 mL). and extracted withDCM three times (10 mL each) and the combined organic layers were driedover MgSO4 and concentrated. The resulting oil was purified bypreparative HPLC. The fractions containing pure product wereconcentrated in vacuo and dried on the lyophilizer to obtain the productas a white solid (40 mg, 24% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.19 (d,J=2 Hz, 1H), 8.84 (dd, J=2 Hz, J=4 Hz, 1H), 8.24 (tt, J=2 Hz, J=4 Hz,1H), 7.46 (q, J=4 Hz, J-2 Hz, 1H), 5.88 (m, 1H), 5.69 (m, 1H), 4.92 (d,J=2 Hz, 2H), 2.94 (s, 3H), 2.65 (m, 1H), 2.01 (m, 2H), 1.85 (m, 2H),1.70 (m, 2H), 1.56 (s, 3H). MS 328 (MH⁺).

Example 2.95a:5-(cyclohex-2-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione

In a N₂-flushed round-bottom flask, were added anhydrous CH₃CN (15 mL),5-(cyclohex-2-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.95b) (580 mg, 1.77 mmol), and the solution was cooled to 0°C. in an ice bath. An ice-cooled solution of ammonium cerium IV nitrate(2531.0 mg, 4.6 mmol) in H₂O (9 mL) was added dropwise and stirred atroom temperature overnight. The mixture was diluted with brine (15 mL)and extracted with EtOAc (3×20 mL). The combined organic phase waswashed again with brine and dried over MgSO₄, and solvents wereevaporated. The obtained compound was used for the next step withoutfurther purification. Yield: (312 mg, 84%). MS 209 (MH⁺).

Example 2.95b:5-(cyclohex-2-en-1-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

To a 20 mL scintillation vial was added5-(cyclohex-2-en-1-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.95c) (565 mg, 1.8 mmol) in dry DMF (5 mL). Sodium hydride(152 mg, 3.80 mmol) was added followed by the addition of methyl iodide(237 mL, 3.8 mmol). The reaction mixture was stirred at room temperaturefor 24 hr, then partitioned between ethyl acetate (20 mL) and water (20mL). The aqueous layer was extracted with ethyl acetate three times (10mL each time) and the combined organic layer was dried over MgSO₄ andconcentrated. The crude compound was purified by preparative HPLC andthe fractions containing pure product were concentrated in vacuo. Theobtained compound was used for the next step without furtherpurification. MS 329 (MH⁺).

Example 2.95c:5-(cyclohex-2-en-1-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

Tert-butyl2-(cyclohex-2-en-1-yl)-2-(3-(4-methoxybenzyl)ureido)propanoate (Example2.95d) (700 mg, 1.8 mmol) in dry DMF (3 mL) was added to a 20 mLscintillation vial, then potassium tert-butoxide (246 mg, 2.2 mmol) wasadded and the reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was partitioned between ethyl acetate(20 mL) and water (20 mL) and the aqueous layer was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over MgSO₄ andconcentrated. The compound was used for the next step without furtherpurification. Yield: (565 mg, 100%). MS 315 (MH⁺)

Example 2.95d: tert-butyl2-(cyclohex-2-en-1-yl)-2-(3-(4-methoxybenzyl)ureido)propanoate

To a 20 mL scintillation vial was added t-butyl2-amino-2-(cyclohex-2-en-1-yl)propanoate (Example 2.95e) (640 mg, 2.84mmol) in dry THF (5 mL). Then p-methoxybenzylisocyanate (463 mg, 2.84mmol) was added and the reaction mixture was stirred at ambienttemperature overnight. The solvent was evaporated, and the residue waspurified by flash chromatography on Biotage 40 g silica column with10%˜50% EtOAc/Hex gradient. The final product was obtained as a whitesolid (700 mg, 64% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J=8 Hz,2H), 6.85 (d, J=8 Hz, 2H), 5.79 (m, 1H), 5.55 (m, 1H), 4.66 (m, 1H),4.26 (m, =2H), 3.79 (s, 3H), 2.70 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H),1.62 (d J=4 Hz, 3H), 1.44 (d J=4 Hz, 9H). MS 389 (MH⁺)

Example 2.95e: tert-butyl 2-amino-2-(cyclohex-2-en-1-yl)propanoate

To a 20 mL scintillation vial was added (E)-tert-butyl2-((4-chlorobenzylidene)amino)-propanoate (Example 2.95f) (1.34 g, 5.0mmol) in dry toluene (5 mL). Then cesium hydroxide (840 mg, 5.0 mmol)was added followed by 3-bromocyclohex-1-ene (890 mg, 5.5 mmol). Thereaction mixture was stirred at 50° C. for 24 hr, then partitionedbetween DCM (10 mL) and water (10 mL). The aqueous layer was extractedwith DCM (3×10 mL) and the combined organic layers were dried over MgSO₄and concentrated. The resulting oil was dissolved in 5 mL of THF andcitric acid (5 mL, 0.5M) was added. The reaction mixture was stirredovernight, then THF was evaporated and the solution was extracted withhexane. The aqueous phase was basified with Na₂CO₃ and extracted withDCM. DCM was evaporated and the residue was purified by preparative HPLCto give the desired product (Yield: 640 mg, 57%). ¹H NMR (400 MHz,CDCl₃) δ 5.84 (m, 1H), 5.42-5.65 (dd, J=Hz, 1H), 2.43 (m, 1H), 1.98 (m,2H), 1.78 (m, 2H), 1.63 (m, =1H), 1.52 (m, 3H), 1.47 (s, 9H), 1.30 (s,3H), 1.22 (s, 2H). MS 226 (MH⁺)

Example 2.95f: (E)-tert-butyl 2-((4-chlorobenzylidene)amino)propanoate

To a 100 mL roundbottom flask was added t-Butyl-alanine (5.8 g, 0.04mol) and p-chlorobenzaldehyde (5.6 g, 0.04 mol) in dry methanol (40 mL).Anhydrous sodium sulfate (11.36 g, 0.08 mol) was added and the reactionmixture was stirred at room temperature for 24 hr. The solvent wasevaporated and the residue was partitioned between DCM (40 mL) and water(40 mL). The aqueous layer was extracted with DCM (3×10 mL) and thecombined organic layers were dried over MgSO₄ and concentrated. Theresulting oil was used for the next step without further purification.Yield: 9.6 g (90%). ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.72 (d, J=8Hz, 2H), 7.38 (d, J=8 Hz, 2H), 4.04 (q, J=8 Hz, 1H), 1.48 (d, J=4 Hz,3H), 1.47 (s, 9H)

Example 2.96:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-3-yl)ethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL), 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.47a) (128 mg, 0.61 mmol), and the reaction mixture was cooledto 0° C. NaH (30 mg, 0.73 mmol), and 2-bromo-1-(1H-pyrrol-3-yl)ethanone(105 mg, 0.73 mmol) were added. The ice bath was removed and thereaction medium was stirred vigorously at room temperature for 18 hr.The reaction was quenched with water and extracted with DCM (3×10 mL).The combined organic phases were washed with brine and dried over MgSO₄,and solvents were evaporated. The residue was purified by flashchromatography using a 12 g Silicycle column and MeOH/DCM gradient aseluant to obtain the pure desired product (30 mg, 15%) as a clear oil.¹H NMR (400 MHz, CDCl₃) δ 9.56 (s, 1H), 7.37-7.39 (m, 1H), 6.73-6.74 (m,1H), 6.58-6.60 (m, 1H), 4.70 (s, 2H), 2.88 (s, 3H), 1.39-1.80 (s&m,10H), 1.04-1.28 (m, 4H). MS 318 (MH⁺).

Example 2.97:1,5-dimethyl-5-((1r,4r)-4-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from1,5-dimethyl-5-(4-methylcyclohexyl)-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.84a) (386 mg, 1 mmol) to obtain product as a colorless oilyfilm. On HPLC this isomer eluted second (60.5 mg, 18% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55(t, J=8 Hz, 2H), 4.93 (s, 2H), 2.79 (s, 3H), 1.78-1.86 (m, 0.5H),1.52-1.71 (m, 4.5H), 1.39-1.50 (m, 1H), 1.37 (s, 3H), 1.21 (m, 1H),0.85-1.02 (m, 3H), 0.83 (d, J=8 Hz, 3H). MS 343 (MH⁺).

Example 2.98:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyridin-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (159mg, 0.75 mmol) and 2-(bromoacetyl)-pyridine hydrobromide (256 mg, 0.91mmol) to obtain the desired product (82 mg, 30%) as a light yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J=5.2 Hz, 1H), 8.01 (d, J=7.6 Hz,1H), 7.82 (t, J=8 Hz, 1H), 7.50 (dd, J=7.2 Hz & 6.0 Hz), 5.19 (s, 2H),2.92 (s, 3H), 1.66 (m, 6H), 1.48 (m, 4H), 1.07 (m, 4H). MS 330 (MH⁺).

Example 2.99:5-cyclopentyl-1-ethyl-5-methyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclopentyl-1-ethyl-5-methylimidazolidine-2,4-dione (Example 2.89a)(100 mg, 0.47 mmol), and 3-(bromoacetyl)-pyridine hydrobromide (267 mg,0.952 mmol), to obtain the pure product as a light yellow oil (50 mg,32%). ¹H NMR (400 MHz, cdcl₃) δ 9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.83 (dd,J=4.8, 1.7 Hz, 1H), 8.24 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 7.46 (ddd,J=8.0, 4.8, 0.9 Hz, 1H), 4.92 (s, 2H), 3.46 (dq, J=14.5, 7.2 Hz, 1H),3.32 (dq, J=14.4, 7.2 Hz, 1H), 2.35-2.24 (m, 1H), 2.00-1.88 (m, 1H),1.79-1.52 (m, 9H), 1.49-1.34 (m, 1H), 1.30 (t, J=7.2 Hz, 3H).

Example 2.100:5-cyclohexyl-3-(2-(2-fluorophenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Anhydrous DMF (8.0 mL), and5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (55 mg,0.26 mmol) were added to an oven-dried, N₂-flushed, small round-bottomflask and the solution was cooled to 0° C. in an ice bath. NaH (15 mg,0.31 mmol), and 2-bromo-1-(2-fluorophenyl)ethanone (105 mg, 0.73 mmol)were added and the reaction was stirred vigorously at room temperaturefor 3 hr. The reaction was quenched with water (10 mL) and extractedwith DCM (3×10 mL). The combined organic phase was washed with brine,dried over MgSO₄, and solvents were evaporated. The residue was purifiedby preparative HPLC to obtain the pure product (15 mg, 16%) as a clearcolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (t, J=8 Hz, 1H), 7.57-7.61(m, 1H), 7.16-7.28 (m, 2H), 4.84 (d, J=3.6 Hz, 2H), 2.01 (s, 3H),1.46-1.86 (s&m, 10H), 1.04-1.25 (m, 4H). MS 347 (MH⁺).

Example 2.101:5-(2-methoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60 starting from5-(2-methoxyphenyl)-1,5-dimethylimidazolidine-2,4-dione (Example 2.60a)(234 mg, 1 mmol) and 2-bromo-1-(1H-pyrrol-2-yl)ethanone (224 mg, 1.2mmol) to obtain the desired product (40 mg, 12%) as an oily film. ¹H NMR(400 MHz, CDCl₃) δ 9.32 (s, 1H), 7.43 (dd, J=7.7, 1.6 Hz, 1H), 7.37(ddd, J=8.2, 7.5, 1.6 Hz, 1H), 7.09-6.99 (m, 3H), 6.89 (dd, J=8.3, 1.1Hz, 1H), 6.33 (dt, J=3.9, 2.5 Hz, 1H), 4.86 (d, J=1.5 Hz, 2H), 3.77 (s,3H), 2.62 (s, 3H), 1.88 (s, 3H). MS 342 (MH⁺).

Example 2.102:5-cyclohexyl-3-(2-(3-fluorophenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (68 mg,0.32 mmol) and bromo-acetyl 3-fluorophenone (108 mg, 0.38 mmol) toobtain the desired product (15 mg, 13%) as a light yellow oil. ¹H NMR(400 MHz, DMSO-d₆) δ 7.73 (m, 1H), 7.63 (m, 1H), 7.46 (m, 1H), 7.26 (m,1H), 4.88 (s, 2H), 2.91 (s, 3H), 1.66 (m, 6H), 1.48 (s & m, 4H), 1.03(m, 4H). MS 347 (MH⁺).

Example 2.103:5-(2-methoxy-4-methylphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(2-methoxy-4-methylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.103a) (117 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 55%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.03-7.97 (m, 2H), 7.65-7.57 (m, 1H), 7.54-7.45 (m, 2H), 7.30(d, J=7.9 Hz, 1H), 6.83 (dd, J=7.9, 0.8 Hz, 1H), 6.71 (s, 1H), 5.02 (d,J=2.9 Hz, 2H), 3.77 (s, 3H), 2.63 (s, 3H), 2.36 (s, 3H), 1.88 (s, 3H).MS 367 (MH⁺).

Example 2.103a:5-(2-methoxy-4-methylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-(2-methoxy-4-methylphenyl)-5-methylimidazolidine-2,4-dione (Example2.103b) (234 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1 mmol)to obtain the desired product (250 mg, 71%) as a white solid. ¹H NMR isconsistent with structure. MS 353 (MH⁺).

Example 2.103b:5-(2-methoxy-4-methylphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(2-methoxy-4-methylphenyl)ethanone (820 mg, 5 mmol) to obtain thedesired product (800 mg, 68%) as a white solid. ¹H NMR is consistentwith structure. MS 235 (MH⁺).

Example 2.104:5-(2,4-dimethoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(2,4-dimethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.104a) (307 mg, 0.83 mmol) and methyl iodide (62 uL, 1.0 mmol)to obtain product as a white powder (63 mg, 20% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.07 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz,2H), 7.37 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.57 (s, 1H), 5.02 (s,2H), 3.76 (s, 3H), 3.69 (s, 3H), 2.47 (s, 3H), 1.72 (s, 3H). MS 383(MH⁺).

Example 2.104a:5-(2,4-dimethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(2,4-dimethoxy-phenyl)-5-methylimidazolidine-2,4-dione (Example2.104b) (250 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1 mmol) toobtain product as a white powder (307.5 mg, 84% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.33 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H),7.57 (t, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 1H), 6.57 (s, 1H), 6.52 (d, J=8Hz, 1H), 4.97 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 1.70 (s, 3H). MS 368(MH⁺).

Example 2.104b: 5-(2,4-dimethoxy-phenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2,4-dimethoxyphenyl)ethanone (1.08 g, 6 mmol) to obtain product as awhite powder (1.07 g, 71% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s,1H), 7.84 (s, 1H), 7.25 (d, J=8 Hz, 1H), 6.55 (s, 1H), 6.49 (d, J=8 Hz,2H), 3.74 (s, 3H), 3.67 (s, 3H), 1.57 (s, 3H). MS 251 (MH⁺).

Example 2.105:5-(cyclohexylmethyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

To5-(cyclohexylmethyl)-1,5-dimethyl-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione (Example 2.105a) (53.2 mg, 138 uM) was addedEtOH (2 mL) and HCl 6N (4 mL) and the reaction mixture was refluxedunder N₂ for 2 hours. The reaction mixture was diluted with water (10mL), extracted with Et₂O (3×10 mL) and the combined organic phase waswashed with brine, dried over MgSO₄, and concentrated, to afford thepure product (45.1 mg, 97%) as a colourless oily film. ¹H NMR (400 MHz,CDCl₃) δ 7.96-7.94 (m, 2H), 7.61-7.57 (m, 1H), 7.49-7.45 (m, 2H), 4.95(d, J=17.6, 1H), 4.90 (d, J=17.6, 1H), 2.88 (s, 3H), 1.82 (dd, J=6.4,J=15.2, 1H), 1.65-1.56 (m, 6H), 1.43 (s, 3H), 1.34-1.17 (m, 3H),1.14-1.06 (m, 1H), 1.00-0.85 (m, 2H). MS 343 (MH⁺).

Example 2.105a:5-(cyclohexylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (5.0 mL),1,5-dimethyl-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105b) (140 mg, 482 umol), and at 0° C. NaH (30.0 mg, 750umol), and after a few minutes stirring at room temperature(bromomethyl)cyclohexane (100 uL, 723 umol). The reaction medium wasstirred vigorously at room temperature for 4 hours and extracted withH₂O/EtOAc (3×). Combined organic phases were washed with brine and driedover MgSO₄, and solvents were evaporated. The residue was purified byflash chromatography using a 40 g Silicycle column and a DCM/EtOAcgradient as eluant to obtain the pure product (53.2 mg, 29%). ¹H NMR(400 MHz, CDCl₃) δ 7.57-7.55 (m, 2H), 7.36-7.30 (m, 3H), 4.01-3.98 (m,2H), 3.88 (d, J=4.0, 2H), 3.79-3.72 (m, 2H), 2.82 (s, 3H), 1.79 (dd,J=6.4, J=14.8, 1H), 1.64-1.49 (m, 5H), 1.50 (dd, J=5.2, J=14.4, 1H),1.24 (s, 3H), 1.19-1.04 (m, 4H), 0.96-0.85 (m, 2H). MS 387 (MH⁺).

Example 2.105b:1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (13.0 mL),1-methyl-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105c) (500 mg, 1.8 mmol), and at 0° C. NaH (80.0 mg, 2.0mmol), and after 15 minutes stirring MeI (200 uL, 3.21 mmol). Thereaction medium was stirred vigorously at room temperature overnight andextracted with H₂O/EtOAc (3×). Combined organic phases were washed withbrine and dried over MgSO₄, and solvents were evaporated. The residuewas purified by flash chromatography using a 80 g Silicycle column and aDCM/EtOAc gradient as eluant to obtain the pure product (140 mg, 27%).¹H NMR (400 MHz, DMSO-d₆) δ 7.38-7.33 (m, 5H), 3.96-3.92 (m, 3H),3.73-3.65 (m, 4H), 2.78 (s, 3H), 1.20 (d, J=6.8, 3H). MS 291 (MH⁺).

Example 2.105c:1-methyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

In a 250 mL round-bottom flask, equipped with a 40 mL Dean-Stark trap, areflux condenser, and a drying tube were added1-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione (Example 2.105d)(7.74 g, 33.3 mmol), anhydrous benzene (150.0 mL), ethylene glycol (3mL, 53.2 mmol), and p-toluenesulfonic acid (128 mg, 0.74 mmol). Thereaction mixture was heated at 135° C. (oil bath temperature) overnight,and the reaction was monitored by LCMS and ¹H-NMR showing at that point40% product. Benzene (150.0 mL, and 60 mL) and ethylene glycol (56 mL,992 mmol and 40 mL, 709 mmol) were added again twice as well asp-toluenesulfonic acid (256 mg, 1.49 mmol) once and the reaction mixturewas further refluxed another night to allow the reaction to go tocompletion (by ¹H-NMR). The reaction mixture was extracted withsaturated NaHCO₃/EtOAc (3×). Combined organic phases were washed withbrine and dried over MgSO₄, and solvents were evaporated to obtain afterdrying the pure product (8.2 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ7.58-7.55 (m, 2H), 7.39-7.33 (m, 3H), 4.04-4.00 (m, 2H), 3.90 (s, 2H),3.84 (s, 2H), 3.80-3.77 (m, 2H). MS 277 (MH⁺).

Example 2.105d: 1-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

In an oven-dried, N₂-flushed, 500 mL round-bottom flask, were addedanhydrous DMF (260.0 mL), commercially available1-methylimidazolidine-2,4-dione (10 g, 87.6 mmol), K₂CO₃ (13.3 g, 96.2mmol), and 2-bromo-1-phenylethanone (20.9 g, 105.0 mmol). The reactionmedium was stirred vigorously at room temperature overnight andextracted with H₂O/EtOAc (2×) and H₂O/Hexanes (1×). Combined organicphases were washed with brine and dried over MgSO₄, and solvents wereevaporated. The residue was purified by flash chromatography using a 330g Silicycle column and a Hexanes/EtOAc gradient followed by DCM/EtOAcgradient as eluants to obtain the pure product (7.74 g, 38%). ¹H-NMR(400 MHz, CDCl₃) δ 7.98-7.96 (m, 2H), 7.65-7.61 (m, 1H), 7.52-7.48 (m,2H), 4.94 (s, 2H), 4.03 (s, 2H), 3.06 (s, 3H). MS 233 (MH⁺).

Example 2.106:5-(cyclobutylmethyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from5-(cyclobutylmethyl)-1,5-dimethyl-3-(2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.137), except the reaction medium was only heated at 50° C.for 1 hour, to obtain the desired product (31.9 mg). ¹H NMR (400 MHz,d₆-DMSO) δ 8.07-8.03 (m, 2H), 7.75-7.69 (m, 1H), 7.61-7.55 (m, 2H), 4.99(d, J=18.1 Hz, 1H), 4.94 (d, J=18.1 Hz, 1H), 2.80 (s, 3H), 2.24-2.14 (m,2H), 1.97-1.85 (m, 2H), 1.85-1.77 (m, 2H), 1.76-1.54 (m, 3H), 1.33 (s,3H). MS 315 (MH⁺).

Example 2.107:5-(cyclohex-2-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

To a 20 mL scintillation vial was added5-(cyclohex-2-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.95a) (108 mg, 0.5 mmol) in dry DMF (5 mL) with potassium carbonate(140 mg, 1.0 mmol). Next, alpha-bromoacetophenone (120 mg, 0.60 mmol)was added and the reaction mixture was stirred at room temperature for24 hr. DCM (10 mL) and water (10 mL) were added and the aqueous layerwas extracted with DCM (10 mL×3). The combined organic layers were driedover MgSO₄ and concentrated in vacuo. The resulting oil was purified bypreparative HPLC. The fractions containing pure product wereconcentrated in vacuo giving a white solid (40 mg) (24% yield). ¹H NMR(400 MHz, CDCL₃) δ 7.96 (dd, J=2 Hz, J=8 Hz, 2H), 7.61 (t, J=8 Hz, 1H),7.49 (t, J=8 Hz, 1H), 5.88 (m, 1H), 5.73 (m, 1H), 4.92 (s, 2H), 2.94 (s,3H), 2.65 (m, 1H), 2.01 (m, 2H), 1.85 (m, 2H), 1.61 (m, 2H), 1.55 (s,3H). MS 327 (MH⁺).

Example 2.108:5-((1R,4R)-bicyclo[2.2.1]hept-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(bicyclo[2.2.1]hept-5-en-2-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.88a) (162 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (eluted first on HPLC) (65 mg, 39%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.93 (m, 2H), 7.64-7.58 (m, 1H),7.53-7.45 (m, 2H), 6.12 (dd, J=5.7, 3.1 Hz, 1H), 5.87 (dd, J=5.7, 2.9Hz, 1H), 4.87 (q, J=17.4 Hz, 2H), 2.99 (s, 3H), 2.87 (s, 1H), 2.80 (s,1H), 2.60-2.52 (m, 1H), 1.83 (dd, J=9.5, 3.8 Hz, 1H), 1.78-1.70 (m, 1H),1.49-1.40 (m, 4H), 1.29 (d, J=8.3 Hz, 1H). MS 339 (MH⁺).

Example 2.109:5-cyclohexyl-3-(2-(furan-2-yl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner to Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (100.0mg, 476 umol), and commercially available 2-bromo-1-(furan-2-yl)ethanone(129 mg, 683 umol), to obtain the desired product. ¹H NMR (400 MHz,d₆-DMSO) δ 8.10 (dd, J=1.7, 0.7 Hz, 1H), 7.66 (dd, J=3.7, 0.7 Hz, 1H),6.80 (dd, J=3.7, 1.7 Hz, 1H), 4.75 (s, 2H), 2.82 (s, 3H), 1.79-1.66 (m,4H), 1.66-1.56 (m, 2H), 1.38 (s, 3H), 1.37-1.28 (m, 1H), 1.26-1.13 (m,2H), 1.06 (dd, J=15.2, 9.9 Hz, 1H), 1.00-0.87 (m, 1H). MS 319 (MH⁺).

Example 2.110:5-(2-fluorophenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(2-fluorophenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.110a) (245 mg, 0.75 mmol) and methyl iodide (56 uL, 0.9 mmol)to obtain the desired product as a white powder (121.5 mg, 48% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=8 Hz, 2H), 7.71 (t, J=8 Hz, 1H),7.62 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 2H), 7.49 (m, 1H), 7.32 (t, J=8Hz, 1H), 7.255 (dd, J=8 Hz, J=12 Hz, 1H), 5.07 (s, 2H), 2.62 (s, 3H),1.86 (s, 3H). MS 341 (MH⁺).

Example 2.110a:5-(2-fluorophenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(2-fluorophenyl)-5-methylimidazolidine-2,4-dione (Example 2.110b) (208mg, 1 mmol) and 2-bromoacetophenone (239 mg, 1.2 mmol) to obtain thedesired product as a white powder (246 mg, 75% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 8.85 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H),7.59 (m, 3H), 7.45 (m, 1H), 7.23 (m, 2H), 5.02 (s, 2H), 1.82 (s, 3H). MS327 (MH⁺).

Example 2.110b: 5-(2-fluorophenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2-fluorophenyl)-ethanone (728 uL, 6 mmol) to obtain the desiredproduct as a white powder (966 mg, 77% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 10.85 (s, 1H), 8.31 (s, 1H), 7.51 (t, J=8 Hz, 1H), 7.415 (dd, J=8 Hz,J=12 Hz, 1H), 7.20 (m, 2H), 1.69 (s, 3H). MS 209 (MH⁺).

Example 2.111:1,5-dimethyl-5-(2-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-methyl-5-(2-methyl-cyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.111a) (499 mg, 1.52 mmol) and methyl iodide (114 uL, 1.83mmol) to obtain the desired product as a white powder of mixture of 4pairs of diastereomers (179 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 4.94(d, J=6 Hz, 2H), 2.81 (s, 1H), 2.79 (s, 2H), 1.55-2.01 (m, 5H),1.39-1.80 (m, 5H), 1.45 (m, 2H), 1.41 (s, 2H), 1.38 (s, 1H), 1.33 (m,2H), 1.19 (m, 1H), 0.95 (d, J=8 Hz, 1H), 0.76 (d, J=8 Hz, 2H). MS 343(MH⁺).

Example 2.111a:5-methyl-5-(2-methylcyclohexyl)-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-methyl-5-(2-methyl-cyclohexyl)imidazolidine-2,4-dione (111b) (420 mg,2 mmol) and 2-bromoacetophenone (478 mg, 2.4 mmol) to obtain the desiredproduct as a white powder of mixture of 4 pairs of diastereomers (499mg, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 0.3H), 8.03 (s,0.7H), 8.02 (d, J=8 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H),4.91 (s, 2H), 1.97-2.12 (m, 1H), 1.63-1.84 (m, 2H), 1.34-1.59 (m, 5H),1.32 (s, 1H), 1.31 (s, 2H), 1.26 (m, 1H), 1.13 (m, 1H), 0.90 (t, J=8 Hz,3H). MS 329 (MH⁺).

Example 2.111b: 5-methyl-5-(2-methylcyclohexyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2-methylcyclohexyl)-ethanone (Example 2.111c) (3 g, 21.43 mmol) toobtain the desired product as a white powder of mixture of 4 pairs ofdiastereomers (2.51 g, 56% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.56(bs, 1H), 7.90 (s, 0.3H), 7.56 (s, 0.7H), 1.91-2.09 (m, 1H), 1.30-1.75(m, 7H), 1.21 (s, 1H), 1.20 (s, 2H), 0.95-1.17 (m, 2H), 0.86 (d, J=8 Hz,2H), 0.82 (d, J=8 Hz, 0.6H), 0.74 (d, J=8 Hz, 0.3H), 0.72 (d, J=8 Hz,0.1H). MS 211 (MH⁺).

Example 2.111c: 1-(2-methylcyclohexyl)-ethanone

Prepared in a similar manner as described in Example 2.59e starting from2-methylcyclohexane-carboxylic acid (cis- and trans-mixture of isomers)(2.815 mL, 20 mmol) to obtain the desired product as a colorless oilconsisting of two pairs of diastereomers (2:1 ratio by NMR analysis) (3g, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.45 (dt, J=4 Hz, J=12 Hz, 1H),2.23 (m, 1H), 2.03 (s, 3H), 1.45-1.66 (m, 5H), 1.35 (m, 2H), 1.14 (m,2H), 0.76 (d, J=8 Hz, 3H). MS N/A.

Example 2.112:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(1H-pyrazol-4-yl)ethyl)imidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added3-(2-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-hydroxyethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.112a) followed by 2 mL DCM and Dess-Martin periodinane (0.240g, 0.56 mmol). The reaction was stirred for 2 hours. 10 mL ether, 5 mLsaturated NaHCO₃, and 5 mL saturated Na₂S₂O₃ were added and the mixturewas stirred for 1 hour. The layers were separated and the organic layerwas washed with 5 mL saturated NaHCO₃, brine and dried with Na₂SO₄. Thesolvent was evaporated, and the residue was purified by columnchromatography utilizing a Silicycle column (12 g) and elution with0-70% ethyl acetate/hexanes. 130 mg of3-(2-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-oxoethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dionewas isolated as an off white semi-solid.

The compound was dissolved in 1 mL dioxane and 1 mL concentrated HCl andstirred at 100° C. until the deprotection was complete. The reactionmixture was neutralized with saturated NaHCO₃, and extracted with ethylacetate (3×10 mL). The combined organics were dried with Na₂SO₄. Thesolvent was evaporated, and the residue was purified by columnchromatography utilizing a Silicycle column (12 g) and elution with20-100% ethyl acetate/hexane to afford 23 mg (20%) of the title compoundas an off white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 8.58(s, 1H), 8.04 (s, 1H), 4.66 (s, 2H), 2.79 (s, 3H), 1.81-1.52 (m, 6H),1.42-1.23 (m, 4H), 1.22-0.86 (m, 4H); MS 319 (MH⁺).

Example 2.112a:3-(2-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-hydroxyethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

To an oven dried, N₂-flushed, small round bottom flask was added4-bromo-1-(tert-butyl)-1H-pyrazole (0.396 g, 1.95 mmol). The flask wassealed and purged with nitrogen. 5 mL anhydrous THF was added and thereaction was cooled to −78° C. n-Butyl lithium (0.93 mL, 2.24 mmol) wasadded and the reaction was stirred at −78° C. for 30 minutes.2-(4-cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetaldehyde(112b) (0.446 g, 1.77 mmol) in 3 mL was then added to the flask at −78°C. The reaction was stirred for 2 hours at −78° C. and quenched withwater. The mixture was extracted with ethyl acetate (3×10 mL). Thecombined organics were dried with Na₂SO₄. The solvent was evaporated,and the residue was purified by column chromatography utilizing aSilicycle column (12 g) and elution with 20-100% ethyl acetate/hexane toafford 200 mg (50%) of product as an off white solid.

Example 2.112 b:2-(4-cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetaldehyde

3-allyl-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example2.112c) (12.1 g, 48.3 mmol) was added to a 250 mL round bottom flaskfollowed by 150 mL DCM. The flask was cooled to −78° C. under nitrogenfor five minutes. The nitrogen and septum were removed and ozone wasbubbled through the solution for 1 h when the reaction turned blue. Thereaction was purged with nitrogen for 20 minutes. Dimethyl sulfide (30.0g, 483.0 mmol) was added and the reaction was stirred overnight. Thesolvent was evaporated, and the residue was purified by columnchromatography utilizing a Silicycle column (100 g) and elution with0-50% ethyl acetate/hexane to afford 7.5 g (61%) of the title compoundas an oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 4.34 (s, 2H), 2.76(s, 3H), 1.78-1.47 (m, 6H), 1.41-1.23 (m, 4H), 1.22-0.97 (m, 3H), 0.85(m, 1H).

Example 2.112c: 3-allyl-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

To an oven dried, N₂-flushed, 250 mL round bottom flask was added5-cyclohexyl-5-methylimidazolidine-2,4-dione (Example 2.47d) (10.1 g,51.5 mmol), K₂CO₃ (7.8 g, 56.6 mmol), 50 mL DMF and allyl bromide (4.4mL, 51.5 mmol). The reaction was stirred at ambient temperature for 2hours and water was added with stirring. The white precipitate wasfiltered and dried to afford 12.48 g (97%) of3-allyl-5-cyclohexyl-5-methylimidazolidine-2,4-dione as a white solid.

To an oven dried, N₂-flushed, 250 mL round bottom flask was added3-allyl-5-cyclohexyl-5-methylimidazolidine-2,4-dione (12.4 g, 52.5mmol), cesium carbonate (26.0 g, 78.7 mmol), 75 mL DMF and methyl iodide(5 mL, 68.3 mmol) neat. After stirring 24 hours at ambient temperaturethe reaction was 70% complete. 150 mL water was added and the mixturewas extracted with ethyl acetate (3×50 mL). The combined organics werewashed with water (1×100 mL), brine and dried with Na₂SO₄. The residuewas re-subjected to the above conditions until the reaction wascomplete. The reaction workup was identical the procedure above. 12.2grams (93%) of the title compound was isolated as an oil. ¹H-NMR (400MHz, DMSO-d₆) δ 5.87-5.67 (m, 1H), 5.09 (ddq, J=22.0, 17.2, 1.6 Hz, 2H),4.07-3.86 (m, 2H), 2.78 (s, 3H), 1.80-1.46 (m, 6H), 1.41-1.25 (m, 4H),1.24-0.96 (m, 3H), 0.78-0.68 (m, 1H); MS 251 (MH⁺).

Example 2.113:5-cyclohexyl-3-(2-(3-methoxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (100.0mg, 476 umol), and commercially available2-bromo-1-(3-methoxyphenyl)ethanone (117.0 mg, 686 umol), to obtain thedesired product. ¹H NMR (400 MHz, d₆-DMSO) δ 7.66-7.62 (m, 1H),7.53-7.46 (m, 2H), 7.30-7.26 (m, 1H), 4.95 (s, 2H), 3.83 (s, 3H), 2.82(s, 3H), 1.79-1.66 (m, 4H), 1.66-1.57 (m, 2H), 1.38 (s, 3H), 1.37-1.29(m, 1H), 1.26-1.13 (m, 2H), 1.10-1.01 (m, 1H), 0.98-0.87 (m, 1H). MS 359(MH⁺).

Example 2.114:5-cyclohexyl-3-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (107.0mg, 509 umol), and 2-bromo-1-(3-hydroxy-4-methoxyphenyl)ethanone (114a)(137.0 mg, 559 umol), to obtain the desired product (59.7 mg, 31%). ¹HNMR (400 MHz, d₆-DMSO) δ 9.54 (s, 1H), 7.58 (dd, J=8.5, 2.2 Hz, 1H),7.35 (d, J=2.2 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 4.85 (d, J=18.0 Hz, 1H),4.80 (d, J=18.0 Hz, 1H), 3.86 (s, 3H), 2.81 (s, 3H), 1.79-1.66 (m, 4H),1.65-1.57 (m, 2H), 1.38 (s, 3H), 1.37-1.28 (m, 1H), 1.25-1.12 (m, 2H),1.10-1.01 (m, 1H), 0.99-0.88 (m, 1H). MS 375 (MH⁺).

Example 2.114a: 2-bromo-1-(3-hydroxy-4-methoxyphenyl)ethanone

Prepared in a similar manner as described in Example 2.49a usingcommercially available 1-(3-hydroxy-4-methoxyphenyl)ethanone (1.0 g, 6.0mmol), to obtain the desired product (881.1 mg, 60%). ¹H NMR (400 MHz,d₆-DMSO) δ 9.48 (s, 1H), 7.54 (dd, J=8.5, 2.2 Hz, 1H), 7.37 (d, J=2.2Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 3.86 (s, 3H). MS noionization.

Example 2.115:5-(cyclohex-3-en-1-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60 starting from5-(cyclohex-3-en-1-yl)-1,5-dimethylimidazolidine-2,4-dione (Example2.93a) (42 mg, 0.2 mmol) and 2-bromo-1-(1H-pyrrol-2-yl)ethanone (45 mg,0.22 mmol) to obtain the desired product (12 mg, 20%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ δ 9.32 (s, 1H), 7.07 (m, 1H) 7.05 (m, 1H),6.33 (dt, J=3.9, 2.5 Hz, 1H), 5.69 (s, 2H), 4.92 (d, J=3.2 Hz, 2H),2.98-2.87 (m, 3H), 2.53-2.36 (m, 1H), 2.22-1.94 (m, 4H), 1.92-1.73 (m,1H), 1.53 (d, J=6.6 Hz, 3H), 1.39-1.24 (m, 1H). MS 327 (MH⁺).

Example 2.116:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(1H-pyrazol-5-yl)ethyl)imidazolidine-2,4-dione

To an oven dried, N₂-flushed 25 mL round bottom flask was added1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Example 2.116a) (0.330g, 1.67 mmol). The flask was sealed and purged with nitrogen. 3 mLanhydrous THF was added and the flask was cooled to −78° C. 1.8 Mn-butyl lithium (0.930 mL, 1.67 mmol) was added and the reaction wasstirred at −78° C. for 30 minutes.2-(4-Cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-methoxy-N-methylacetamide(116b) (0.451 g, 1.45 mmol) in 1 mL THF was added to the solution at−78° C. and the reaction was stirred for 4 hours. The reaction wasquenched at −78° C. with 1 mL water. The mixture was extracted withethyl acetate (3×10 mL) and dried with Na₂SO₄. The solvent was removedto afford 50 mg of5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)ethyl)imidazolidine-2,4-dione.The residue was dissolved in 1 mL dioxane and 1 mL 6 M HCl and heated at50° C. for 4 h. The solvent was evaporated and the residue was purifiedby HPLC chromatography using acetonitrile and water as eluents to afford4 mg of the title compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ7.92 (s, 1H), 6.79 (s, 1H), 4.78 (s, 2H), 2.79 (s, 3H), 1.77-1.54 (m,6H), 1.39-0.75 (m, 8H); MS 319 (MH⁺).

Example 2.116a: 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole Example2.116b:2-(4-cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-methoxy-N-methylacetamide

To an oven dried, N₂-flushed 100 mL round bottom flask was added5-cyclohexyl-5-methylimidazolidine-2,4-dione (Example 2.47d) (6.77 g,32.9 mmol), K₂CO₃ (6.80 g, 49.3 mmol) 32 mL of anhydrous DMF andcommercially available 2-chloro-N-methoxy-N-methylacetamide (4.74 g,34.5 mmol). The reaction was stirred at 50° C. for 12 h. The reactionwas cooled and 70 mL water was added with stirring. The precipitate wasfiltered and dried to afford 8.9 g (92%) of2-(4-cyclohexyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-N-methoxy-N-methylacetamideas a white solid.

To an oven dried, N₂-flushed 100 mL round bottom flask was added2-(4-cyclohexyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-N-methoxy-N-methylacetamide(8.90 g, 29.9 mmol), Cs₂CO₃ (13.65 g, 41.9 mmol), 30 mL DMF and methyliodide (2 mL, 31.4 mmol). The reaction was stirred for 24 hours and 60mL water was added. The mixture was extracted with ether (3×50 mL). Thecombined organic layers were washed with water (1×100 mL), brine anddried with Na₂SO₄. The solvent was evaporated, and the residue waspurified by column chromatography utilizing a Silicycle column (120 g)and elution with 20-70% ethyl acetate/hexane to afford 8.2 g (88%) ofthe title compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 4.28(s, 2H), 3.73 (s, 3H), 3.10 (s, 3H), 2.78 (s 3H), 1.79-1.49 (m, 6H),1.39-1.25 (m, 4H), 1.23-0.82 (m, 4H); MS 312 (MH⁺).

Example 2.117:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(m-tolyl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.43 using5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (100.0mg, 476 umol), and commercially available 2-bromo-1-m-tolylethanone(146.0 mg, 685 umol), to obtain the desired product (109.6 mg, 67%). ¹HNMR (400 MHz, d₆-DMSO) δ 7.87-7.80 (m, 2H), 7.53 (d, J=7.5 Hz, 1H), 7.46(t, J=7.6 Hz, 1H), 4.95 (d, J=18.1 Hz, 1H), 4.90 (d, J=18.1 Hz, 1H),2.82 (s, 3H), 2.39 (s, 3H), 1.79-1.66 (m, 4H), 1.66-1.57 (m, 2H), 1.38(s, 3H), 1.37-1.28 (m, 1H), 1.25-1.13 (m, 2H), 1.10-1.01 (m, 1H),0.99-0.87 (m, 1H). MS 343 (MH⁺).

Example 2.118:5-cyclohexyl-3-(2-(1-ethyl-1H-pyrazol-4-yl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (0.143g, 0.67 mmol), K₂CO₃ (0.141 g, 1.02 mmol),0.5 mL DMF and2-bromo-1-(1-ethyl-1H-pyrazol-4-yl)ethanone (Example 2.118a) (0.145 g,0.67 mmol) to afford 0.107 g (46%) of the title compound as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.56 (s 1H), 8.05 (s, 1H), 4.65 (s,2H), 4.19 (q, J=7.3 Hz, 2H), 2.80 (s, 3H), 1.80-1.54 (m, 6H), 1.48-1.26(m, 7H), 1.25-0.85 (m, 4H); MS 347 (MH⁺).

Example 2.118a: 2-bromo-1-(1-ethyl-1H-pyrazol-4-yl)ethanone

To an oven dried, 100 mL round bottom flask was added ethyl1H-pyrazole-4-carboxylate (3.2 g, 22.8 mmol), Cs₂CO₃ (8.9 g, 27.4 mmol),20 mL DMF and ethyl iodide (2 mL, 23.9 mmol). The reaction was stirredfor 50° C. for 12 h. 20 mL water was added and the mixture was extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith water (1×20 mL), brine and dried with Na₂SO₄ to afford 3.6 grams ofethyl 1-ethyl-1H-pyrazole-4-carboxylate as an oil.

To a 100 mL round bottom flask was added ethyl1-ethyl-1H-pyrazole-4-carboxylate (3.6 g, 21.4 mmol), 20 mL methanol and10 M NaOH (8.6 mL, 85.6 mmol). The reaction was refluxed for 2 hours andcooled to room temperature. The pH was adjusted to approximately 2 with6 M HCl. The white precipitate was collected and dried to afford 2.4 g(80%) of 1-ethyl-1H-pyrazole-4-carboxylic acid as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 4.15 (q,J=10 Hz, 3H), 1.36 (t, J=10 Hz, 4H)

To an oven dried, N₂-flushed 100 mL round bottom flask was added1-ethyl-1H-pyrazole-4-carboxylic acid (0.978 g, 6.98 mmol), 10 mL DCM,oxalyl chloride (2.4 mL, 27.9 mmol) and 1 drop of DMF. The reaction wasstirred for 1 h at 45° C. The solvent was removed. Toluene was added andevaporated 2 times. The residue was dissolved in 10 mL acetonitrile andcooled to 0° C. Trimethylsilyldiazomethane (10.5 mL, 20.9 mmol) wasadded and the reaction as stirred for 12 h at ambient temperature. Thesolution was cooled to 0° C. and 2.2 mL of HBr was added. The reactionwas stirred for 1 hour and the solvent was evaporated. The residue wasdissolved in 20 mL ethyl acetate and washed with saturated NaHCO₃, brineand dried with Na₂SO₄ to afford 1.3 grams of2-bromo-1-(1-ethyl-1H-pyrazol-4-yl)ethanone (118a) as an oil. MS 217(MH⁺). The compound was used without any further purification.

Example 2.119:5-((2S,5R)-2-isopropyl-5-methylcyclohexyl)-1-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a from5-((2S,5R)-2-isopropyl-5-methylcyclohexyl)imidazolidine-2,4-dione(Example 2.119a) (107.1 mg, 449 umol), K₂CO₃ (107.0 mg, 774 umol), and2-bromo-1-phenylethanone (97.5 mg, 490 umol), to obtain the desiredcompound (22.5 mg, 14%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.79 (s, 1H),8.09-8.00 (m, 2H), 7.74-7.69 (m, 1H), 7.61-7.55 (m, 2H), 4.95 (s, 2H),1.77-1.64 (m, 3H), 1.63-1.53 (m, 3H), 1.45-1.32 (m, 3H), 1.03-0.91 (m,2H), 0.88 (d, J=6.4 Hz, 3H), 0.84 (d, J=3.7 Hz, 3H), 0.82 (d, J=3.5 Hz,3H). MS—Does not ionize well.

Example 2.119a:5-((2S,5R)-2-isopropyl-5-methylcyclohexyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b from(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde (Example 2.119b)(752.3 mg, 4.47 mmol), except the reaction medium was heated at 55° C.for 18 hours only and the work-up was a combination of precipitatefiltration and extraction using H₂O/EtOAc, to obtain the desiredcompound (691.9 mg, 65%) which was used without further purification.The proton NMR is consistent with the structure, showing also additionalpeaks related to starting material. MS no ionization.

Example 2.119b: (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde

To a suspension of (methoxymethyl)triphenylphosphonium chloride (9.33 g,19.45 mmol) in dry THF (60 mL) at 0° C., was added a 2 M solution ofn-BuLi in hexanes (13.61 mL, 27.22 mmol) via syringe over 10 min. Thered solution was stirred for 30 min at 0° C. and (−)-menthone (3.00 g,19.45 mmol) was added over 5 min. The reaction mixture was stirred for10 h at room temperature and then quenched with 1 N HCl, extracted withdiethyl ether (3×), dried over anhydrous magnesium sulfate andconcentrated partially under reduced pressure. The residue was filteredto remove the solid triphenyl phosphine oxide and the filtrate wasconcentrated under reduced pressure. The enol ether obtained was thendissolved in 20 mL of chloroform and 3 mL of 12 N HCl was added. Thesolution was stirred 4 h at room temperature and chloroform wasevaporated. Diethyl ether and water were added and the aqueous phase wasextracted with diethyl ether (2×) and the combined organic layers weredried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography eluting withethyl acetate:hexanes (1:20) to yield 2.76 g (84%) of the desiredaldehyde. ¹H NMR (CDCl₃, 400 MHz): δ 9.49 (d, 1H, J=4.4 Hz), 2.24 (tt,1H, J=11.5, 4.4 Hz), 1.82-1.63 (m, 4H), 1.54 (tt, 1H, J=11.8, 3.2 Hz),1.47-1.26 (m, 2H), 1.17-0.88 (m, 2H), 0.92 (d, 6H, J=6.5 Hz), 0.80 (d,3H, J=7.5 Hz). MS 168 (MH⁺)

Example 2.120:5-(2-(benzyloxy)phenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(2-benzyloxy)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.120a) (207 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 47%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.76 (dt, J=3.6, 1.4 Hz, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.54-7.49(m, 2H), 7.49-7.34 (m, 7H), 7.09-6.98 (m, 2H), 4.94 (dd, J=79.2, 10.0Hz, 2H), 3.97 (dd, J=55.6, 17.8 Hz, 2H), 2.64 (s, 3H), 1.88 (s, 3H). MS429 (MH⁺).

Example 2.120a:5-(2-benzyloxy)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-(2-benzyloxy)-5-methylimidazolidine-2,4-dione (296 mg, 1 mmol) and2-bromo-1-phenylethanone (199 mg, 1 mmol) to obtain the desired5-(2-benzyloxy)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(250 mg, 71%) as a white solid. ¹H NMR is consistent with structure. MS415 (MH⁺).

Example 2.120b: 5-(2-benzyloxy)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(2-(benzyloxy)phenyl)ethanone (1130 mg, 5 mmol) to obtain the desiredproduct (1 g, 68%) as a white solid. MS 297 (MH⁺).

Example 2.121:(5S,6S,9R)-6-isopropyl-9-methyl-3-(2-oxo-2-phenylethyl)-1,3-diazaspiro[4.5]decane-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from(5S,6S,9R)-6-isopropyl-9-methyl-1,3-diazaspiro[4.5]decane-2,4-dione(0.35 g, 1.58 mmol), triethylamine (0.41 g, 3.15 mmol) and2-bromo-1-phenylethanone (0.33 g, 1.66 mmol) in 2 mL of DCM to afford137 mg (25%) of the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.79 (s, 1H), 8.06-8.04 (m, 2H), 7.73-7.70 (m, 1H), 7.60-7.56(m, 2H), 4.95 (s, 2H), 1.75-1.23 (m, 8H), 1.02-0.79 (m, 10H); MS 343(MH⁺).

Example 2.121a:(5S,6S,9R)-6-isopropyl-9-methyl-1,3-diazaspiro[4.5]decane-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from(−)-menthone (1.46 g, 9.5 mmol), (NH₄)₂CO₃ (2.82 g, 30 mmol) and KCN(0.68 g, 10.5 mmol) in 12 mL of methanol and 9 mL H₂O to obtain the 1.6grams (76%) of the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 10.53 (s, 1H), 8.29 (s, 1H), 1.69-1.41 (m, 6H), 1.33-1.22 (m,2H), 0.93-0.76 (m, 10H); MS 225 (MH⁺).

Example 2.122:5-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(6,6-dimethylbicyclo-[3.1.1]hept-2-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.138a) (24.5 mg, 0.1 mmol) and 2-bromoacetophenone (24 mg,0.12 mmol). Gives 11.5 mg (31.4% yield) of product as a white powder. OnHPLC this isomer eluted second. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J=8Hz, 2H), 7.61 (t, J=8 Hz, 1H), 7.49 (t, J=8 Hz, 2H), 5.79 (m, 1H), 4.92(s, 2H), 2.80 (s, 3H), 2.46 (m, 1H), 2.37 (m, 2H), 2.17 (t, J=4 Hz, 1H),2.12 (m, 1H), 1.63 (s, 3H), 1.33 (s, 3H), 1.07 (d, J=8 Hz, 1H), 0.77 (s,3H). MS 367 (MH⁺).

Example 2.123:5-(2-chlorobenzyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

5-(2-chlorobenzyl)-1,5-dimethylimidazolidine-2,4-dione (Example2.123a)(249 μmol, 63 mg) and K₂CO₃ (374 μmol, 52 mg) were placed in avial with dry DMF (2 mL) and stirred for 1 minute.2-bromo-1-phenylethanone (274 μmol, 55 mg) was added and stirred at roomtemperature overnight. The reaction was quenched with 10% citricacid/water solution (10 mL) and an additional 20 mL of water was added.The reaction mixture was extracted with DCM (3×10 mL), washed withbrine, then dried over MgSO₄, filtered, and concentrated in vacuo. Thefinal product was purified by silica gel flash chromatography (10→60%EtOAc/hexanes gradient). to give a 61% yield of product. ¹H NMR (400MHz, d₆-DMSO) δ 8.02-7.98 (m, 2H), 7.71-7.66 (m, 1H), 7.57-7.51 (m, 2H),7.44-7.39 (m, 1H), 7.28-7.25 (m, 2H), 7.25-7.20 (m, 1H), 4.86 (d, J=18.2Hz, 1H), 4.81 (d, J=18.1 Hz, 1H), 3.26 (d, J=2.7 Hz, 2H), 2.87 (s, 3H),1.52 (s, 3H). MS 371 (MH⁺).

Example 2.123a: 5-(2-chlorobenzyl)-1,5-dimethylimidazolidine-2,4-dione

5-(2-chlorobenzyl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.123b) (250 μmol, 93 mg) was dissolved in ACN (2.5 mL) andwater (0.5 mL). Ceric ammonium nitrate (525 μmol, 288 mg) was added andthe mixture was allowed to stir at room temperature overnight.Additional ceric ammonium nitrate (125 μmol, 69 mg) was added withstirring at room temperature overnight. Saturated NaHCO₃/water solution(10 mL) was added and stirred at room temperature for 30 minutes, thenthe salts were filtered off and washed with a 50:50 mixture ofwater:ACN. The filtrate was concentrated to dryness and the residueextracted with hot THF (3×5 mL). THF was removed in vacuo to give alight orange solid, 63 mg, ˜90% pure by ¹H NMR (balance is unreactedstarting material). Used in the subsequent step without furtherpurification.

Example 2.123b:5-(2-chlorobenzyl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

5-(2-chlorobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione (Example2.123c) (895 μmol, 309 mg) and NaH (60% dispersion in mineral oil, 1.97mmol, 79 mg) were added to a vial with dry DMF (2 mL) under nitrogen.The reaction was stirred for 10 minutes until bubbling ceased then MeI(2.24 mmol, 140 μL) was added and the reaction was stirred overnight atroom temperature. Water (30 mL) was slowly added followed by 10% citricacid/water solution (5 mL). The resulting precipitate was filtered,washed with water and dried in a vacuum oven overnight at 50° C. to givea beige solid, 319 mg, 96% yield. MS 373 (MH⁺). 1H NMR is consistentwith structure.

Example 2.123c:5-(2-chlorobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione

5-(2-chlorobenzyl)imidazolidine-2,4-dione (Example 2.123d) (1.0 mmol,225 mg), dry DMF (2 mL) and K₂CO₃ (1.0 mmol, 139 mg) were combined in avial and stirred at room temperature for 1 minute, then 4-methoxybenzylchloride (1.0 mmol, 136 μL) was added and stirred 48 h at roomtemperature. Water (30 mL) was added and the resulting precipitate wasfiltered and washed with water, then dried in a vacuum oven overnight at50° C. to afford 309 mg of product as a white solid, 90% yield. MS 345(MH⁺). ¹H NMR is consistent with structure.

Example 2.123d: 5-(2-chlorobenzyl)imidazolidine-2,4-dione

Prepared in a similar manner to Example 2.46d fromL-2-amino-3-(2-chlorophenyl) propanoic acid (4.63 mmol, 923 mg). 715 mgof a white solid, 65% yield. MS 225 (MH⁺). ¹H NMR is consistent withstructure.

Example 2.124:3-(2-(3-chlorophenyl)-2-oxoethyl)-5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, were addedanhydrous DMF (8.0 mL), 5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione(Example 2.47a) (62 mg, 0.29 mmol), and at 0° C. NaH (15 mg, 0.35 mmol),and 2-bromo-1-(3-chlorophenyl)ethanone (82 mg, 0.35 mmol). The reactionmedium was stirred vigorously at room temperature for 3 hr, andextracted with H₂O/DCM (3×). Combined organic phases were washed withbrine and dried over MgSO₄, and solvents were evaporated. The residuewas purified by prep HPLC to obtain the pure product (30 mg, 28%) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (t, J=2.0 Hz, 1H), 7.57 (d,J=7.6 Hz, 1H), 7.82 (dt, J=7.6 Hz & 0.8 Hz, 1H), 7.42 (t, J=8 Hz, 1H),4.87 (s, 2H), 2.91 (s, 3H), 1.45˜1.86 (s&m, 10H), 1.02˜1.24 (m, 4H). MS363 (MH⁺).

Example 2.125:1,5-dimethyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)-5-phenethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from1,5-dimethyl-5-phenethylimidazolidine-2,4-dione (Example 2.125a) (153mg, 0.66 mmol) and 3-(bromoacetyl)-pyridine hydrobromide (222 mg, 0.79mmol), to obtain the pure desired product as a light yellow oil (30 mg,13%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (d, J=1.6 Hz, 1H), 8.83 (dd,J=4.4 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8 Hz & 4.8 Hz, 1H),7.27 (m, 2H), 7.17 (m, 3H), 4.91 (s, 2H), 2.90 (s, 3H), 2.62 (m, 1H),2.53 (m, 1H), 2.24 (m, 1H), 1.80 (m, 1H), 1.48 (s, 3H). MS 352 (MH⁺).

Example 2.125a: 1,5-dimethyl-5-phenethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from3-(4-methoxybenzyl)-1,5-dimethyl-5-phenethylimidazolidine-2,4-dione(Example 2.125b) (2.75 mmol, 640 g) and a solution of ammonium ceriumnitrate (3.9 g, 7.15 mmol) in water (20 mL), to obtain the pure productas a light brown solid (320 mg, 80%). The reaction mixture had stirredat room temperature for 18 hrs. Both LCMS and analytical TLC showedcompletion of the reaction (no MS ionization). After ACN was evaporated,the resulting water layer was extracted with 30% ACN in DCM (30 mL×3).The organic layers were combined, washed with brine, and then dried overMgSO₄. After the solvent was evaporated, the resulting light brown oilwas purified on Biotage 40 g silica column with elute 10%˜40% EtOAc/Hex(Rf˜0.2 in 30% EtOAc/Hex).

Example 2.125b:3-(4-methoxybenzyl)-1,5-dimethyl-5-phenethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from3-(4-methoxybenzyl)-5-phenethylimidazolidine-2,4-dione (Example 2.125c)(2.96 mmol, 961 mg) in DMF (15 mL) (Example 2.125c), and methyl bromide(7.1 mmol, 442 mL), to obtain the pure product as a white solid (640 mg,61%). MS 353 (MH⁺).

Example 2.125c: 3-(4-methoxybenzyl)-5-phenethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45c starting from(S)-5-phenethylimidazolidine-2,4-dione (Example 2.125d) (900 mg, 4.4mmol) in DMF (25 mL) (Example 2.125d), and para-methoxyl benzyl chloride(1.1 eq, 4.8 mmol, 657 ul), to obtain the pure product as a white solid(961 mg, 67%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 7.25 (m, 2H),7.16 (m, 3H), 6.85 (m, 2H), 4.38 (dd, J=20 Hz & 15.2, 2H), 3.70 (s, 3H),2.57 (m, 2H), 1.98 (s, 1H), 1.79 (m, 1H).

Example 2.125d: (S)-5-phenethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46d starting fromα-homo-phenylalanine (5.18 mmol, 930 mg) in water (25 mL), HCl (0.4 mL),and potassium cyanate (26 mmol, 2.1 g), to obtain the pure product as awhite solid (979 mg, 92%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H),7.24 (m, 2H), 7.15 (m, 3H), 6.33 (d, J=8.4 Hz, 1H), 4.00 (m, 1H), 2.55(m, 2H), 1.89 (m, 1H), 1.76 (m, 1H).

Example 2.126:5-(2-methoxy-4,5-dimethylphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(2-methoxy-4,5-dimethylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.126a) (284 mg, 0.77 mmol) and methyl iodide (58 uL, 0.93mmol) to obtain product as a white powder (144 mg, 49% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.07 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.57(t, J=8 Hz, 2H), 7.21 (s, 1H), 6.83 (s, 1H), 5.02 (s, 2H), 3.65 (s, 3H),2.47 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.73 (s, 3H). MS 381 (MH⁺).

Example 2.126a:5-(2-methoxy-4,5-dimethylphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(2-methoxy-4,5-dimethylphenyl)-5-methylimidazolidine-2,4-dione(Example 2.126b) (248 mg, 1 mmol) and 2-bromoacetophenone (200 mg, 1mmol) to obtain product as a white powder (284 mg, 78% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.69 (t, J=8Hz, 1H), 7.55 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 4.97 (s, 2H),3.68 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H), 1.70 (s, 3H). MS 367 (MH⁺).

Example 2.126b:5-(2-methoxy-4,5-dimethylphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2-methoxy-4,5-dimethylphenyl)ethanone (1068 mg, 6 mmol) to obtainproduct as a white powder (1.35 g, 91% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 10.49 (s, 1H), 7.83 (s, 1H), 7.08 (s, 1H), 6.81 (s, 1H), 3.64 (s, 3H),2.18 (s, 3H), 2.14 (s, 3H), 1.58 (s, 3H). MS 249 (MH⁺).

Example 2.127:1,5-dimethyl-3-(2-oxo-2-phenylethyl)-5-(pyridin-2-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-methyl-3-(2-oxo-2-phenylethyl)-5-(pyridin-2-yl)imidazolidine-2,4-dione(Example 2.127a) (155 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 62%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.65 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.02-7.95 (m, 2H),7.83-7.75 (m, 1H), 7.67-7.56 (m, 2H), 7.55-7.47 (m, 2H), 7.30 (ddd,J=7.5, 4.8, 1.1 Hz, 1H), 5.10-4.93 (m, 2H), 2.85 (s, 3H), 1.99 (s, 3H).MS 324 (MH⁺).

Example 2.127a:5-methyl-3-(2-oxo-2-phenylethyl)-5-(pyridin-2-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-methyl-5-(pyridin-2-yl)imidazolidine-2,4-dione (Example 2.127b) (191mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1 mmol) to obtain theproduct (200 mg, 65%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.62-8.55 (m, 1H), 7.96 (dd, J=8.4, 1.3 Hz, 2H), 7.79-7.71 (m, 2H), 7.61(d, J=7.4 Hz, 1H), 7.49 (dd, J=11.7, 4.3 Hz, 2H), 7.33-7.27 (m, 1H),6.46 (s, 1H), 4.96 (s, 2H), 1.91 (s, 3H). MS 310 (MH⁺).

Example 2.127b: 5-methyl-5-(pyridin-2-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-(pyridin-2-yl)ethanone (1210 mg, 10 mmol) to obtain the product (1 g,52%) as a light yellow solid. ¹H NMR is consistent with structure. MS192 (MH⁺).

Example 2.128:(5S,6S,9R)-6-isopropyl-1,9-dimethyl-3-(2-oxo-2-phenylethyl)-1,3-diazaspiro[4.5]decane-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from(5S,6S,9R)-6-isopropyl-9-methyl-1,3-diazaspiro[4.5]decane-2,4-dione(Example 2.121) (0.13 g, 0.38 mmol), K₂CO₃ (0.080 g, 0.570 mmol) andmethyl iodide (0.070 g, 0.49 mmol) in 5 mL DMF to afford 21 mg (16%) ofthe title compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ8.05-8.03 (m, 2H), 7.74-7.70 (m, 1H), 7.60-7.86 (m, 2H), 5.01 (s, 2H),3.11 (s, 3H), 1.94-1.71 (m, 6H), 1.60-1.46 (m, 2H), 1.08-0.98 (m, 1H),0.86-0.80 (m, 6H); MS 357 (MH⁺).

Example 2.129:5-cyclopentyl-3-(2-(3-fluorophenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-cyclopentyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.45a) (87mg, 443 umol), and 2-bromo-1-(3-fluorophenyl)ethanone (118 mg, 544umol), to obtain the pure product as an oily film. ¹H NMR (400 MHz,CDCl₃) δ 7.73-7.70 (m, 1H), 7.63-7.60 (m, 1H), 7.48-7.43 (m, 1H),7.31-7.26 (m, 1H), 4.87 (s, 2H), 2.91 (s, 3H), 2.31-2.22 (m, 1H),1.89-1.81 (m, 1H), 1.72-1.51 (m, 6H), 1.48 (s, 3H), 1.42-1.35 (m, 1H).MS 333 (MH⁺).

Example 2.130:5-cyclohexyl-1,5-dimethyl-3-(2-oxo-2-(pyrimidin-5-yl)ethyl)imidazolidine-2,4-dione

Anhydrous DCM (3.0 mL),5-cyclohexyl-3-(2-hydroxy-2-(pyrimidin-5-yl)ethyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.130a) (52 mg, 0.16 mmol), and pyridinium dichromate (88 mg,0.23 mmol) were added to a N₂-flushed, small round-bottom flask. Afterstirring at room temperature for 18 hrs. the reaction mixture wasdiluted with H₂O and DCM. The organic layer was dried over MgSO₄, andsolvents were evaporated. The residue was purified by mass-triggeredHPLC to obtain the desired product (20 mg, 40%) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 9.42 (s, 1H), 9.26 (s, 2H), 4.89 (s, 2H), 2.92 (s,3H), 1.45-1.86 (s&m, 10H), 1.01-1.26 (m, 4H). MS 331 (MH⁺).

Example 2.130a:5-cyclohexyl-3-(2-hydroxy-2-(pyrimidin-5-yl)ethyl)-1,5-dimethylimidazolidine-2,4-dione

In an oven-dried, N₂-flushed, small round-bottom flask, was added5-bromopyrimidine (229 mg, 1.44 mmol) in THF (20 mL) at roomtemperature. The solution was cooled down to −78° C., then nBuLi wasadded dropwise. After stirring for 2 min at −78° C.,2-(4-cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetaldehyde(Example 2.112b) in THF (2 mL) (275 mg, 1.09 mmol) was added dropwiseover 5 mins. The resulting reaction mixture was stirred at −78° C. for 1hr and quenched with cold water (10 mL). The mixture was extracted withDCM (3×25 mL) and the combined organic layer was dried over MgSO₄, andconcentrated. The residue was purified by mass-triggered HPLC to obtainthe desired product (100 mg, 30%) as a clear oil. MS 333 (MH⁺). H¹-NMRis consistent with the structure.

Example 2.131:5-cyclobutyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-cyclobutyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.131a) (0.10 g, 0.37 mmol), K₂CO₃ (0.61 g, 0.44 mmol) andmethyl iodide (0.062 g, 0.44 mmol) in 0.5 mL DMF to afford 63 mg (57%)of the title compound as a semi-solid. ¹H-NMR (400 MHz, DMSO-d₆) δ8.07-8.04 (m, 2H), 7.74-7.70 (m, 1H) 7.60-7.56 (m, 2H), 4.99 (s, 2H),2.85-2.75 (m, 4H), 2.37-2.30 (m, 1H), 1.89-1.73 (m, 4H), 1.66-1.62 (m,1H), 1.29 (s, 3H); MS 301 (MH⁺).

Example 2.131a:5-cyclobutyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-cyclobutyl-5-methylimidazolidine-2,4-dione (Example 2.131b) (0.202 g,1.2 mmol), diisopropylethylamine (0.31 g, 2.4 mmol), andbromoacetophenone (0.26 g, 1.3 mmol) in 2 mL DMF to afford 210 mg (61%)of the title compound as an off white semi-solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.53 (s, 1H), 8.03-8.00 (m, 2H), 7.71-7.61 (m, 1H), 7.57-7.53(m, 2H), 4.89 (s, 2H), 2.65-2.58 (m, 1H), 1.96-1.63 (m, 6H), 1.21 (s,3H); MS 287 (MH⁺).

Example 2.131b: 5-cyclobutyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-cyclobutylethanone (2.19 g, 22.3 mmol), (NH₄)₂CO₃ (6.64 g, 69.2 mmol)and KCN (1.60 g, 24.5 mmol) in 30 mL MeOH and 20 mL of H₂O to afford 3.4g (91%) of the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.03 (s, 1H), 2.58-2.50 (m, 1H), 1.87-1.62 (m, 6H), 1.16 (s,3H); MS 169 (MH⁺).

Example 2.132:5-((3R,5R,7R)-adamantan-1-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-((3R,5R,7R)-adamantan-1-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.132a) (155 mg, 0.5 mmol) and MeI (40 uL, 0.6 mmol) to obtainthe desired product (100 mg, 62%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.96 (dd, J=8.4, 1.3 Hz, 2H), 7.61 (t, J=7.4 Hz, 1H), 7.49 (t,J=7.7 Hz, 2H), 4.90 (d, J=0.7 Hz, 2H), 3.02 (s, 3H), 2.04 (s, 3H),1.98-1.90 (m, 3H), 1.75-1.58 (m, 9H), 1.47 (s, 3H). MS 324 (MH⁺).

Example 2.132a:5-((3R,5R,7R)-adamantan-1-yl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from5-((3R,5R,7R)-adamantan-1-yl)-5-methylimidazolidine-2,4-dione (Example2.132b) (191 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1 mmol)to obtain the desired product (200 mg, 65%) as a light yellow solid. ¹HNMR (400 MHz, CDCl₃ 5.7.99-7.93 (m, 2H), 7.64-7.58 (m, 1H), 7.50 (dd,J=8.2, 7.1 Hz, 2H), 5.41 (s, 1H), 4.89 (s, 2H), 2.11-2.01 (m, 3H), 1.93(dd, J=11.9, 1.7 Hz, 3H), 1.81 (d, J=2.9 Hz, 1H), 1.68 (d, J=16.1 Hz,6H), 1.55-1.51 (m, 2H), 1.48 (s, 3H). MS 310 (MH⁺).

Example 2.132b:5-((3r,5r,7r)-adamantan-1-yl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.60d starting from1-((3R,5R,7R)-adamantan-1-yl)ethanone (1780 mg, 10 mmol) to obtain theproduct (1.6 g, 65%) as a white solid. ¹H NMR is consistent withstructure. MS 249 (MH⁺).

Example 2.133:5-(2,5-diethoxyphenyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(2,5-diethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.133a) (294 mg, 0.74 mmol) and methyl iodide (55 uL, 0.89mmol) to obtain product as a white powder (200.6 mg, 66% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.07 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.57(t, J=8 Hz, 2H), 7.00 (s, 1H), 6.92 (s, 2H), 4.99 (q, J=18 Hz, J=52 Hz,2H), 3.99 (q, J=8 Hz, J=16 Hz, 2H), 3.88 (q, J=8 Hz, J=12 Hz, 2H), 2.49(s, 3H), 1.76 (s, 3H), 1.30 (t, J=8 Hz, 3H), 1.19 (t, J=8 Hz, 3H). MS411 (MH⁺).

Example 2.133a:5-(2,5-diethoxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44a starting from5-(2,5-diethoxyphenyl)-5-methylimidazolidine-2,4-dione (Example 2.133b)(278 mg, 1 mmol) and 2-bromoacetophenone (239 mg, 1.2 mmol) to obtainproduct as a white powder (294 mg, 74% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 8.38 (s, 1H), 8.07 (d, J=8 Hz, 2H), 7.70 (t, J=8 Hz, 1H), 7.57 (t, J=8Hz, 1H), 6.95 (s, 1H), 6.89 (s, 2H), 4.94 (q, J=20 Hz, J=40 Hz, 2H),3.97 (q, J=8 Hz, J=16 Hz, 2H), 3.88 (q, J=8 Hz, J=12 Hz, 2H), 1.73 (s,3H), 1.29 (t, J=8 Hz, 3H), 1.22 (t, J=8 Hz, 3H). MS 397 (MH⁺).

Example 2.133b: 5-(2,5-diethoxyphenyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from1-(2,5-diethoxyphenyl)-ethanone (1248 mg, 6 mmol) to obtain product as awhite powder (1.45 g, 87% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s,1H), 7.87 (s, 1H), 6.87 (m, 3H), 3.95 (q, J=8 Hz, J=16 Hz, 2H), 3.87(dq, J=8 Hz, J=12v, J=20 Hz, 2H), 1.58 (s, 3H), 1.28 (t, J=8v, 3H), 1.23(t, J=8 Hz, 3H). MS 279 (MH⁺).

Example 2.134:5-(cyclopropylmethyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from5-(cyclopropylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.134a) (49.0 mg, 142 umol), except the reaction medium wasonly heated at 50° C. for 1 hour, to obtain the desired product (42.0mg, 98%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.08-8.02 (m, 2H), 7.75-7.68 (m,1H), 7.62-7.53 (m, 2H), 5.00 (s, 2H), 2.85 (s, 3H), 1.88 (dd, J=14.7,6.1 Hz, 1H), 1.52 (dd, J=14.6, 7.6 Hz, 1H), 1.34 (s, 3H), 0.60-0.50 (m,1H), 0.44-0.33 (m, 2H), 0.11-0.05 (m, 1H), 0.04-−0.02 (m, 1H). MS 301(MH⁺).

Example 2.134a:5-(cyclopropylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105a startingfrom1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105b) (148.8 mg, 513 umol) and (bromomethyl)cyclopropane (61uL, 624 umol), except the extracted material was purified by a 40minutes preparative HPLC run using a CH₃CN/H₂O gradient as eluant, toobtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.56 (m, 2H),7.38-7.31 (m, 3H), 4.03-3.96 (m, 2H), 3.93 (d, J=0.6 Hz, 2H), 3.82-3.75(m, 2H), 2.88 (s, 3H), 1.73 (dd, J=14.5, 5.2 Hz, 1H), 1.60-1.52 (m, 1H),1.27 (s, 3H), 0.46-0.36 (m, 2H), 0.34-0.25 (m, 1H), 0.12-−0.02 (m, 2H).MS 345 (MH⁺).

Example 2.135:(S)-5-benzyl-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from(S)-5-benzyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.135a) (0.15 mmol, 47 g) in DMF (5 mL) (Example 2.136a) andiodomethane (0.34 mmol, 20 uL), to obtain the pure desired product as ayellow oil (7 mg, 14%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (m, 2H), 7.59(m, 1H), 7.44 (m, 2H), 7.25 (m, 3H), 7.09 (m, 2H), 4.61 (dd, J=21 Hz &17 Hz, 2H), 2.96 (dd, J=85 Hz & 14 Hz, 2H), 3.00 (s, 3H), 1.57 (s, 3H).No ionization.

Example 2.135a:(S)-5-benzyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from(S)-5-benzyl-5-methylimidazolidine-2,4-dione (Example 2.135b) (100 mg,0.49 mmol) (Example 2.135b) in dry DMF (10 mL) α-bromoacetophenone (118mg, 0.59 mmol), to obtain the pure product as a light yellow oil (47 mg,29%). MS 324 (MH⁺)

Example 2.135b: (S)-5-benzyl-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46d starting fromα-methylphenylalanine (2 mmol, 358 mg), water (10 mL), concentratedhydrochloric acid (0.2 mL) and potassium cyanate (10 mmol, 810 mg), toobtain the pure product as a white solid (200 mg, 50%). MS 205 (MH⁺).

Example 2.136:5-(2-fluorobenzyl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

To a 20 mL scintillation vial was added5-(2-fluorobenzyl)-1,5-dimethylimidazolidine-2,4-dione (Example 2.136a)(90 mg, 0.38 mmol) in dry DMF (2 mL) and potassium carbonate (140 mg,1.0 mmol) followed by alpha-bromoacetophenone (100 mg, 0.50 mmol). Thereaction mixture was stirred at room temperature for 24 hr, thenpartitioned between DCM (10 mL) and water (10 mL). The aqueous layer wasextracted with DCM (10 mL×3) and the combined organic layer was driedover MgSO₄ and concentrated. The resulting oil was purified by prepHPLC. The fractions containing pure product were concentrated in vacuoand dried in lyophilizer to afford the product as a white solid (40 mg,30% yield). ¹H NMR (400 MHz, CDCL₃) δ 7.91 (d, J=8 Hz, 2H), 7.60 (t, J=8Hz, 1H), 7.47 (t, J=8 Hz, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 7.03 (m, 2H),4.74 (dd, J=20 Hz, J=8 Hz, 2H), 3.17 (dd, J=16 Hz, J=24 Hz, 2H), 2.98(d, J=2 Hz, 3H), 1.64 (s, 3H). MS 355 (MH⁺).

Example 2.136a: 5-(2-fluorobenzyl)-1,5-dimethylimidazolidine-2,4-dione

In a N₂-flushed round-bottom flask, were added anhydrous CH₃CN (10 mL),5-(2-fluorobenzyl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.136b) (249 mg, 0.7 mmol), and the solution was cooled to 0°C. in an ice bath ammonium cerium IV nitrate (1000.0 mg, 1.8 mmol) inH₂O (6 mL) was added dropwise and the reaction mixture was stirredvigorously at room temperature overnight. The solution was diluted withbrine and extracted with EtOAc (3×10 mL). The combined organic phase waswashed again with brine, dried over MgSO₄, and concentrated. Theresulting compound was used for the next step without furtherpurification. Yield: (90 mg, 54%). MS 237 (MH⁺)

Example 2.136b:5-(2-fluorobenzyl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

To a 20 mL scintillation vial were added5-(2-fluorobenzyl)-3-(4-methoxybenzyl)-imidazolidine-2,4-dione (Example2.136c) (249 mg, 0.76 mmol) in dry DMF (3 mL) followed by sodium hydride(91 mg, 2.28 mmol) and methyl iodide (190 uL, 3.0 mmol). The reactionmixture was stirred at room temperature for 24 hr then partitionedbetween DCM (10 mL) and water (10 mL). The aqueous layer was extractedwith DCM three times (10 mL each time) and the combined organic layerswere dried over MgSO₄ and concentrated. The resulting oil was purifiedby preparative HPLC. The fractions containing pure product wereconcentrated in vacuo and dried in lyophilizer. Yield: 249 mg (92%). MS357 (MH⁺).

Example 2.136c:5-(2-fluorobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione

To a 20 mL scintillation vial was added5-(2-fluorobenzyl)imidazolidine-2,4-dione (Example 2.136d) (168 mg, 0.81mmol) in dry DMF (3 mL) followed by potassium carbonate (223 mg, 1.6mmol) and 4-Br-benzylchloride (126 mg, 0.81 mmol). The reaction mixturewas stirring at room temperature for 24 hr and the reaction mixture waspartitioned between DCM (10 mL) and water (10 mL). The aqueous layer wasextracted with DCM three times (10 mL×3) and the combined all organiclayers were dried over MgSO₄ and concentrated. The resulting oil waspurified by preparative HPLC. The fractions containing pure product wereconcentrated in vacuo and dried in lyophilizer. Yield: 249 mg (93%). MS329 (MH⁺).

Example 2.136d: 5-(2-fluorobenzyl)imidazolidine-2,4-dione

A mixture of o-F-phenylalanine hydrochloride (220 mg, 1 mmol) and KNCO(405 mg, 5 mmol) in 5 mL of H₂O was refluxed for 2 hr. After cooling,conc. HCl (1.6 mL) was added to the reaction mixture and the whole wasrefluxed for another 30 min. Crystals precipitated after reactionmixture cooled and were collected by filtration. Yield: 168 mg (81%). ¹HNMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 7.92 (s, 1H), 7.27 (m, 2H), 7.12(m, 2H), 4.29 (t, J=4.8 Hz, 1H), 2.96 (m, 2H). MS 209 (MH⁺).

Example 2.137:5-(cyclobutylmethyl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105a startingfrom1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105b) (150.0 mg, 517 umol) and (bromomethyl)cyclobutane (70uL, 623 umol), except the extracted material was purified bymass-spectroscopy-triggered preparative HPLC, to obtain the desiredproduct. ¹H NMR (400 MHz, d₆-DMSO) δ 7.43-7.32 (m, 5H), 3.99-3.93 (m,2H), 3.76-3.64 (m, 4H), 2.70 (s, 3H), 2.00-1.90 (m, 1H), 1.82-1.73 (m,3H), 1.73-1.50 (m, 5H), 1.15 (s, 3H). MS 359 (MH⁺).

Example 2.138:5-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.138a) (94 mg, 0.376 mmol) and2-bromo-1-(1H-pyrrol-2-yl)ethanone (78 mg, 0.56 mmol). Gives 82.8 mg(62% yield) of product as a white powder. On HPLC this isomer was elutedsecond. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 7.15 (s, 2H), 6.22(s, 1H), 4.615 (q, J=16 Hz, J=20 Hz, 2H), 2.70 (s, 3H), 2.30 (t, J=8 Hz,1H), 1.94-2.07 (m, 2H), 1.66-1.77 (m, 4H), 1.48 (m, 1H), 1.34 (s, 3H),1.27 (d, J=8 Hz, 1H), 1.17 (s, 3H), 0.78 (s, 3H). MS 358 (MH⁺).

Example 2.138a:5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.138b) (620 mg, 1.67 mmol) and a solution of ammonium ceriumnitrate (2.388 g, 4.35 mmol) in water (10 mL) to obtain product as awhite powder of mixture of 2 pairs of diastereomers (285 mg, 68% yield).¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 2.58 (s, 3H), 2.21 (t, J=8Hz, 1H), 1.94-2.04 (mm, 2H), 1.67-1.76 (mm, 3H), 1.559 (t, J=6, 1H),1.43 (m, 1H), 1.30 (d, J=8 Hz, 1H), 1.23 and 1.24 (2s, 3H), 1.16 and1.17 (2s, 3H), 0.76 (s, 3H). MS 251 (MH⁺).

Example 2.138b:5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione(Example 2.138c) (539 mg, 1.57 mmol) and Methyliodide (216 uL, 3.46mmol) to obtain product as a colorless oil of mixture of 2 pairs ofdiastereomers 6:1 ratio (620 mg, 100% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 7.14 (d, J=8 Hz, 2H), 6.86 (d, J=8 Hz, 2H), 4.40 and 4.43 (2s, 2H),3.69 and 3.70 (2s, 3H), 2.80 (s, 0.4H), 2.64 (s, 2.6H), 2.24 (m, 1H),1.98 (m, 1H), 1.50-1.68 (m, 4H), 1.35-1.41 (m, 2H), 1.27 (s, 2.6H), 1.24(s, 0.4H), 1.11 (s, 0.4H), 1.06 (s, 2.6H), 1.45 (d, J=6 Hz, 1H), 0.73(s, 3H). MS 371 (MH⁺).

Example 2.138c:5-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-3-(4-methoxybenzyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46c starting from5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)imidazolidine-2,4-dione(Example 2.138d) (808.5 mg, 3.64 mmol) and 4-methoxybenzyl chloride (543uL, 4 mmol) to obtain product as a white powder (539 mg, 43% yield) ofmixture of 2 pairs of diastereomers 2:1 ratio. ¹H NMR (400 MHz, DMSO-d₆)δ 8.36 (s, 0.3H), 8.16 (s, 0.7H), 7.14 (d, J=8 Hz, 2H), 6.85 (d, J=8 Hz,2H), 4.39 (m, 2H), 3.96 (m, 1H), 3.69 (s, 2H), 3.70 (s, 1H), 2.27 (m,1H), 1.95 (m, 1H), 1.88 (t, J=5.2, 1H), 1.62-1.75 (m, 4H), 1.28-1.48 (m,3H), 1.14 (s, 2H), 1.08 (s, 1H), 0.75 (s, 2H), 0.73 (s, 1H). MS 343(MH⁺).

Example 2.138d:5-(6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44b starting from(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-carbaldehyde (Example2.138e) (893.6 mg, 5.88 mmol) to obtain product as a white powder (808.5mg, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 7.79 (s, 1H),3.86 (d, J=6.4 Hz, 1H), 2.25 (m, 1H), 2.01 (m, 1H), 1.91 (t, J=5.2, 1H),1.62-1.75 (mm, 4H), 1.34-1.53 (mm, 4H), 1.16 (s, 3H), 0.77 (s, 3H). MS223 (MH⁺).

Example 2.138e:(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-carbaldehyde

To a mixture of oxalyl chloride (1 mL, 11 mmol) in 25 mL of anhydrousDCM under N₂ atmosphere cooled to −70° C. was added dropwise anhydrousDMSO (1.56 mL, 22 mmol) in 5 mL of anhydrous DCM. Reaction mixture wasallowed to stir for 2 minutes and then added((1S,2S,5S)-(−)-trans-myrtanol (1.58 mL, 10 mmol) in 10 mL anhydrous DCMwithin 5 min. Reaction mixture was stirred for 15 min and then was addedEt₃N (6.95 mL, 50 mmol). Reaction mixture was stirred additional 5 min,then warmed up to room temperature. Formed white precipitate was pouredin to 50 mL of water and extracted with DCM (3×20 mL). Combined organicfractions were washed with brine, dried over MgSO₄ and concentrated invacuum. Crude aldehydes 90% clean by LCMS analysis was used in to nextstep without purification (1.47 g, 97% yield, as colorless oil). ¹H NMR(400 MHz, DMSO-d₆) δ 9.55 (s, 1H), 2.72 (m, 2H), 2.20 (t, J=8, 1H),2.00-2.09 (m, 2H), 1.78-1.86 (m, 3H), 1.49-1.57 (m, 1H), 1.21 (s, 3H),0.83 (s, 3H). MS N/A.

Example 2.139:2-(4-cyclohexyl-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-N-phenylacetamide

Prepared in a similar manner to Example 2.45 from5-cyclohexyl-1,5-dimethylimidazolidine-2,4-dione (Example 2.47a) (204μmol, 43 mg) and 2-chloro-N-phenylacetamide (265 μmol, 45 mg). Whitesolid, 54 mg, 77% yield. ¹H NMR (400 MHz, d₆-DMSO) δ 10.22 (s, 1H),7.54-7.50 (m, 2H), 7.32-7.26 (m, 2H), 7.07-7.01 (m, 1H), 4.17 (s, 2H),2.78 (s, 3H), 1.79-1.47 (m, 6H), 1.33 (s, 3H), 1.38-0.82 (m, 6H). MS 344(MH⁺).

Example 2.140:5-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

The two enantiomers of Example 2.54 (55 mg, 154 umol) were separated bychiral chromatography utilizing hexane/isopropanol/methanol as thesolvent system. The most potent enantiomer was the second compound toelute. Twenty purified fractions were combined and the solventsevaporated. The residue was dissolved in ethanol and evaporated threetimes to remove undesirable solvents. The material was dissolved inethanol and filtered through a cotton plug. The ethanol was removed andthe compound was dried on the lyophilizer and vacuum oven at 40° C. toobtain the desired pure enantiomer (24.8 mg, 45%). ¹H-NMR (400 MHz,DMSO-d₆) δ 10.01 (br s, 1H), 7.49-7.47 (m, 1H), 7.38-7.34 (m, 1H),7.32-7.31 (m, 1H), 7.10-7.07 (m, 1H), 4.88 (s, 2H), 2.81 (s, 3H), 2.37(s, 1H), 2.17 (s, 1H), 1.84 (m, 1H), 1.50-1.47 (m, 2H), 1.43 (s, 3H),1.37-1.31 (m, 1H), 1.27-1.21 (m, 2H), 1.16-1.14 (m, 2H), 1.02-0.99 (m,1H); MS 357 (MH⁺).

Example 2.141:5-(2-ethoxyphenyl)-1-ethyl-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70 starting from5-(2-hydroxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Example 2.141a) (32 mg, 0.1 mmol) and EtBr (17 uL, 0.23 mmol) to obtainthe desired product (5 mg, 13%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (dt, J=8.5, 1.7 Hz, 2H), 7.66-7.58 (m, 1H), 7.54-7.43 (m,3H), 7.39-7.31 (m, 1H), 7.01 (td, J=7.6, 1.1 Hz, 1H), 6.85 (dd, J=8.2,0.9 Hz, 1H), 5.00 (d, J=0.8 Hz, 2H), 4.11-3.85 (m, 2H), 3.13 (qd, J=7.2,1.6 Hz, 2H), 1.95 (s, 3H), 1.36 (t, J=7.0 Hz, 4H), 0.92 (t, J=7.2 Hz,3H). MS 381 (MH⁺).

Example 2.141a:5-(2-hydroxyphenyl)-5-methyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.70a starting from2-(4-methyl-2,5-dioxoimidazolidin-4-yl)phenyl acetate (Example 2.141b)(248 mg, 1 mmol) and 2-bromo-1-phenylethanone (199 mg, 1 mmol) to obtainthe product (100 mg, 31%) as a white solid. ¹H NMR is consistent withstructure. MS 325 (MH⁺).

Example 2.141b: 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)phenyl acetate

Prepared in a similar manner as described in Example 2.60d starting from2-acetylphenyl acetate (890 mg, 5 mmol) to obtain the desired product(0.8 g, 64%) as a white solid. MS 249 (MH⁺).

Example 2.142:5-((1S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.142a) (210 mg, 0.89 mmol) and2-bromo-1-(3-hydroxyphenyl)ethanone (193 mg, 0.9 mmol). Gives 96.7 mg(29% yield) of product as a yellowish oily film as a mixture of 2 pairsof diastereomers 2:1 ratio. ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (bs, 1H),7.47 (d, J=8 Hz, 2H), 7.36 (t, J=8 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J=8Hz, 1H), 6.15 (dt, J=8 Hz, J=32 Hz, 1H), 5.96 (m, 1H), 4.86 (m, 2H),2.78 (s, 2H), 2.71 (s, 1H), 2.49 (m, 1H), 2.29 (m, 1H), 2.14 (m, 1H),1.39-1.73 (m, 4H), 1.29 (s, 1H), 1.27 (s, 2H), 1.11-1.21 (m, 2H). MS 369(MH⁺).

Example 2.142a:5-(bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.142b) (1.325 g, 3.74 mmol) and a solution of ammonium ceriumnitrate (5.33 g, 9.73 mmol) in water (15 mL) to obtain product as awhite powder of mixture of 2 pairs of diastereomers (419 mg, 48% yield).¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 0.4H), 10.60 (s, 0.6H), 6.12 (m,1H), 5.91 (dt, J=8 Hz, J=32 Hz, 1H), 2.67 (s, 2H), 2.60 (s, 1H), 2.25(m, 1H), 2.01 (m, 1H), 2.14 (m, 1H), 1.26-1.73 (m, 5H), 1.19 (s, 1H),1.16 (s, 2H), 1.10-1.15 (m, 2H). MS 235 (MH⁺).

Example 2.142b:5-(bicyclo[2.2.2]oct-5-en-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.142c) (1.48 g, 4.35 mmol) and methyl iodide (326 uL, 5.22mmol) to obtain product as a colorless oil of mixture of 2 pairs ofdiastereomers (1325 mg, 86% yield). MS 355 (MH⁺).

Example 2.142c:5-(bicyclo[2.2.2]oct-5-en-2-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46c starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-5-methylimidazolidine-2,4-dione (Example2.51b) (1077 mg, 4.89 mmol) and 4-methoxybenzyl chloride (730 uL, 5.38mmol) to obtain product as a white powder (1.48 g, 89% yield) of mixtureof 2 pairs of diastereomers 2:1 ratio. ¹H NMR (400 MHz, DMSO-d₆) δ 7.99(s, 0.4H), 7.88 (s, 0.6H), 7.16 (m, 2H), 6.86 (m, 2H), 6.09 (m, 1H),5.80 (m, 1H), 4.39 (m, 2H), 3.70 (s, 3H), 2.56 (m, 0.5H), 2.40 (m,0.5H), 1.92 (m, 1.5H), 1.66 (m, 1H), 1.35-1.47 (m, 2.5H), 1.20 (s, 1H),1.11 (s, 2H), 1.08 (m, 2H), 0.93 (m, 1H). MS 341 (MH⁺).

Example 2.143:5-((1S,4S)-bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(bicyclo[2.2.2]oct-5-en-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.142a) (210 mg, 0.89 mmol) and2-bromo-1-(1H-pyrrol-2-yl)ethanone (185 mg, 0.98 mmol). Gives 131 mg(43% yield) of product as a yellowish oily film as a mixture of 3 pairsof diastereomers. ¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (bs, 1H), 7.16 (m,2H), 6.22 (m, 1H), 6.15 (dt, J=8 Hz, J=32 Hz, 1H), 5.96 (m, 1H), 4.65(m, 2H), 2.84 (s, 0.5H), 2.78 (s, 2H), 2.70 (s, 0.5H), 2.62 (m, 0.5H),2.43 (m, 0.5H), 2.28 (m, 1H), 2.13 (m, 1H), 1.93 (m, 0.5H), 1.39-1.66(m, 3.5H), 1.45 (s, 0.5H), 1.27 (s, 0.5H),1.26 (s, 2H), 1.11-1.21 (m,2H). MS 342 (MH⁺).

Example 2.144:5-(bicyclo[2.2.2]octan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144a) (150 mg, 0.635 mmol) and2-bromo-1-(3-hydroxyphenyl)ethanone (136 mg, 0.635 mmol). Gives 57.5 mg(29% yield) of product as a yellowish oily film as a mixture of 2 pairsof diastereomers 1:1 ratio. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (bs, 1H),7.46 (t, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.305 (s, 1H), 7.06 (d, J=8Hz, 1H), 4.88 (s, 1H), 4.86 (s, 1H), 2.88 (s, 1.5H), 2.75 (s, 1.5H),1.95-2.09 (m, 2H), 1.81 (m, 1H), 1.56-1.65 (m, 2H), 1.39-1.53 (m, 6H),1.37 (s, 1.5H), 1.36 (s, 1.5H), 1.24-1.34 (m, 2H). MS 371 (MH⁺).

Example 2.144a:5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45a starting from5-(bicyclo[2.2.2]octan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144b) (614 mg, 1.72 mmol) and a solution of ammonium ceriumnitrate (2.46 g, 4.48 mmol) in water (15 mL) to obtain product as awhite powder of mixture of 2 pairs of diastereomers 1:1 ratio (303 mg,75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 0.5H), 10.75 (s,0.5H), 2.78 (s, 1.5H), 2.63 (s, 1.5H), 1.89-1.98 (m, 2H), 1.81 (m, 1H),1.53-1.60 (m, 2H), 1.18-1.44 (m, 8H), 1.27 (s, 1.5H), 1.25 (s, 1.5H). MS237 (MH⁺).

Example 2.144b:5-(bicyclo[2.2.2]octan-2-yl)-3-(4-methoxybenzyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45b starting from5-(bicyclo[2.2.2]octan-2-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione(Example 2.144c) (852 mg, 2.49 mmol) and methyl iodide (187 uL, 3 mmol)to obtain product as a colorless oil of mixture of 2 pairs ofdiastereomers (614.5 mg, 69% yield). MS 357 (MH⁺).

Example 2.144c:5-(bicyclo[2.2.2]octan-2-yl)-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.46c starting from5-(bicyclo[2.2.2]octan-2-yl)-5-methylimidazolidine-2,4-dione (Example2.51b) (927 mg, 4.17 mmol) and 4-methoxybenzyl chloride (623 uL, 4.59mmol) to obtain product as a white powder (852 mg, 60% yield) of mixtureof 2 pairs of diastereomers 1:1 ratio. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52(s, 0.5H), 8.18 (s, 0.5H), 7.16 (m, 2H), 6.86 (d, J=8 Hz, 2H), 4.39 (m,2H), 3.70 (s, 1.5H), 3.69 (s, 1.5H), 1.84 (m, 1H), 1.26-1.66 (m, 10H),1.24 (s, 1.5H), 1.19 (s, 1.5H), 1.02-1.17 (m, 2H). MS 343 (MH⁺).

Example 2.145:(R)-5-((1R,2S,4R)-bicyclo[2.2.2]octan-2-yl)-3-(2-(3-hydroxyphenyl)-2-oxoethyl)-1,5-dimethylimidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.45 starting from5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144a) (150 mg, 0.635 mmol) and2-bromo-1-(3-hydroxyphenyl)ethanone (136 mg, 0.635 mmol). Gives 28.5 mg(12% yield) of product as a yellowish oily film. This isomer was elutedsecond on HPLC column ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (bs, 1H), 7.42(d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J=8 Hz,1H), 4.85 (s, 1H), 2.74 (s, 3H), 1.95-2.09 (m, 2H), 1.56-1.65 (m, 2H),1.39-1.53 (m, 6H), 1.36 (s, 3H), 1.24-1.34 (m, 3H). MS 371 (MH⁺).

Example 2.146:5-((1S,4S)-bicyclo[2.2.2]octan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144a) (150 mg, 0.635 mmol) and2-bromo-1-(1H-pyrrol-2-yl)ethanone (131 mg, 0.69 mmol). Gives 14.7 mg(7% yield) of product as a yellowish oily film. On HPLC this isomereluted first. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (bs, 1H), 7.15 (s, 2H),6.22 (m, 1H), 4.67 (s, 1H), 2.88 (s, 3H), 2.03 (m, 1H), 1.83 (m, 1H),1.58-1.66 (m, 3H), 1.37-1.52 (m, 7H), 1.36 (s, 3H), 1.22-1.34 (m, 1H).MS 344 (MH⁺).

Example 2.147:(R)-5-((1R,2S,4R)-bicyclo[2.2.2]octan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144a) (150 mg, 0.635 mmol) and2-bromo-1-(1H-pyrrol-2-yl)ethanone (131 mg, 0.69 mmol). Gives 35.7 mg(16% yield) of product as a yellowish oily film. On HPLC this isomer wasthe second to elute. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (bs, 1H), 7.15(m, 2H), 6.22 (m, 1H), 4.65 (s, 1H), 2.74 (s, 3H), 2.04 (m, 2H),1.51-1.66 (m, 3H), 1.37-1.52 (m, 5H), 1.35 (s, 3H), 1.19-1.32 (m, 3H).MS 344 (MH⁺).

Example 2.148:5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethyl-3-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.44 starting from5-(bicyclo[2.2.2]octan-2-yl)-1,5-dimethylimidazolidine-2,4-dione(Example 2.144a) (150 mg, 0.635 mmol) and2-bromo-1-(1H-pyrrol-2-yl)ethanone (131 mg, 0.69 mmol). Gives 89.4 mg(41% yield) of product as a yellowish oily film as a mixture of 2 pairsof diastereomers 2:1 ratio.

¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (bs, 1H), 7.15 (m, 2H), 6.22 (m, 1H),4.67 (s, 1H), 4.65 (s, 1H), 2.88 (s, 2H), 2.75 (s, 1H), 2.03 (m, 2H),1.83 (m, 1H), 1.51-1.66 (m, 3H), 1.37-1.52 (m, 5H), 1.36 (s, 2H), 1.35(s, 1H), 1.22-1.34 (m, 2H). MS 344 (MH⁺).

Example 2.149:5-(but-3-en-2-yl)-1,5-dimethyl-3-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105 starting from5-(but-3-en-2-yl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.149a) (80 mg, 0.23 mmol) to obtain product as a colorlessoily film (51 mg, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 2H), 5.53 (m, 1H),5.03-5.26 (m, 2H), 4.96 (s, 2H), 2.80 (s, 3H), 2.39 (m, 1H), 1.60 (d,J=8 Hz, 2.5H), 1.39 (s, 0.4H), 1.34 (s, 2.6H), 1.07 (d, J=8 Hz, 0.25H),0.92 (d, J=8 Hz, 0.25H). MS 345 (MH⁺).

Example 2.149a:5-(but-3-en-2-yl)-1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione

Prepared in a similar manner as described in Example 2.105a startingfrom1,5-dimethyl-3-((2-phenyl-1,3-dioxolan-2-yl)methyl)imidazolidine-2,4-dione(Example 2.105b) (100 mg, 0.34 mmol) to obtain product as a colorlessoil (80 mg, 68% yield). MS 345 (MH⁺).

3.1) Biological Assay

The present compounds are useful as modulators of TRPM8. The activity ofTRPM8 can be readily monitored in cell based assays using fluorescentcalcium-sensitive dyes, membrane potential dyes, or sodium-sensitivedyes. The activity of TRPM8 can also be monitored withelectrophysiological set-ups, such as patch-clamping and two-electrodevoltage clamping. A mammalian cell line derivative which stablyexpresses TRPM8 was used in biological assays in association withtesting the present compounds with cool-tasting or -feeling properties(Servant et al. US 2007/0259354 A1 and references cited therein).Typical compound concentrations tested were 50 μM, 20 μM, 10 μM, 5 μM, 2μM, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, 0.01 μM, and other concentrationpoints in between. The present compounds have shown strong activity asagonists of hTRPM8. Assay results for compounds are illustrated in Table3.1 below. Specifically, the Compounds listed in Table 3.1, i.e.,Compounds 3.A1 to Compounds 3.G1 are the specific compounds as describedabove. For example, Compound 3.A1 is Example 3.1.

TABLE 3.1 EC50 EC50 Ratio Observed Example (uM) (WS3) [m/z + 1] 3.A10.013 581.6 304.2 3.A2 0.010 577.8 288.2 3.A3 0.028 221.2 320.2 3.A40.041 132.4 294.1 3.A5 0.056 116.2 306.2 3.A6 0.080 99.6 306.2 3.A70.056 86.8 288.2 3.A8 0.061 84.4 300.2 3.A9 0.087 66.5 320.2 3.A10 0.05962.5 294.1 3.B1 0.105 45.5 304.2 3.B2 0.138 38.1 288.2 3.B3 0.363 34.1302.2 3.B4 0.230 26.5 289.2 3.B5 0.161 25.0 286.2 3.B6 0.193 20.6 277.23.B7 0.257 18.6 306.2 3.B8 0.420 16.3 302.2 3.B9 0.398 15.3 306.2 3.B100.309 13.7 314.2 3.C1 0.254 13.0 289.2 3.C2 0.471 12.3 294.1 3.C3 0.59111.6 302.2 3.C4 0.449 10.0 277.2 3.C5 0.504 9.4 304.2 3.C6 0.489 9.2294.1 3.C7 0.662 8.2 302.2 3.C8 1.369 5.5 302.2 3.C9 0.621 5.3 290.23.C10 0.954 4.7 274.2 3.D1 1.085 4.7 296.2 3.D2 1.914 4.5 276.2 3.D31.035 4.5 274.2 3.D4 1.427 4.3 318.2 3.D5 2.181 4.1 288.2 3.D6 2.348 3.9282.1 3.D7 1.026 3.9 300.2 3.D8 1.395 3.9 274.2 3.D9 2.348 3.8 276.23.D10 2.362 3.5 300.1 3.E1 1.555 3.1 282.1 3.E2 1.337 2.8 308.1 3.E31.942 2.8 272.1 3.E4 1.781 2.7 300.2 3.E5 1.211 2.5 280.1 3.E6 4.468 2.5296.1 3.E7 2.156 1.9 320.2 3.E8 4.740 1.9 296.1 3.E9 3.161 1.8 334.23.E10 2.923 1.7 308.1 3.F1 2.385 1.6 274.2 3.F2 1.784 1.6 280.1 3.F32.863 1.4 280.2 3.F4 5.938 1.4 276.2 3.F5 3.084 1.4 289.2 3.F6 3.213 1.3320.2 3.F7 3.507 1.2 308.1 3.F8 4.173 1.1 290.2 3.F9 3.391 1.0 286.23.F10 6.103 1.0 318.2 3.G1 6.242 1.0 275.2

3.2) Sensory Studies

Two typical sensory studies are described below each followed by a tablesummarizing sensory results of selected compounds of the invention(Tables 3.2 and 3.3).

Formulation:

All samples made with Low Sodium Buffer (LSB) pH˜7.1 and contain 0.1%ethanol.

General Protocol:

The test is a cool line scale test with timed 30 seconds interval.Compounds are rated on a 15 point line scale where 45 μM WS-3(N-Ethyl-p-menthane-3-carboxamide) is ranked as a 5 in cool intensity.The present compound was tested to determine at what concentration thecooling intensity is equivalent to 45 μM WS-3. In each test, thepanelist was presented with a 0 μM control sample, a 45 μM WS-3 controlsample and the experimental compound sample and asked to rate thecooling intensity of each sample. Panelists were also asked to ratebitterness. In the table below there was no significant bitternessdetected unless otherwise noted. Also, in the table below, n representsthe number of tests completed for a given experiment (# panelists×#repetitions).

Conclusions:

Panelists found 5 μM COMPOUND 3.2 was significantly more cooling than 0μM WS-3 (p<0.05) and not significantly different in cooling than 45 μMWS-3 (p>0.05). There were no significant bitter offtastes in any of thesamples (p>0.05).

TABLE 3.2 Average Cooling, n = 30 (15 Panelists × 2 rep). Tukey's Value= 0.926 (α = 0.05). Treatment Average SD St Er Tukey (5%)  0 μM WS-3 0.71.5 0.3 a  5 μM Compound 3.2 4.0 1.8 0.3 b 45 μM WS-3 4.5 1.5 0.3 b

TABLE 3.3 Average Bitterness, n = 30 (15 Panelists × 2 rep). Tukey'sValue = 0.317 (α = 0.05). Treatment Average SD St Er Tukey (5%)  0 μMWS-3 0.2 0.5 0.1 a  5 μM Compound 3.2 0.4 0.8 0.1 a 45 μM WS-3 0.5 1.10.2 aTable 3.4 summarizes addition sensory studies that were conducted onthese compounds.

TABLE 3.4 Summary or related sensory results. Example Sensory result n3.A1 Panelists found 5 uM 58758115 was significantly more cooling than 0uM WS-3 (p < 0.05) 24 and not significantly different in cooling 45 uMWS-3 (p > 0.05) 3.A2 Panelists found 5 uM 57962022 was significantlymore cooling than 0 uM WS-3 (p < 0.05) 30 and not significantlydifferent in cooling 45 uM WS-3 (p > 0.05) 3.A6 Panelists found 5 uM58751264 was significantly more cooling than 0 uM WS-3 (p < 0.05) 20 andnot significantly different in cooling 45 uM WS-3 (p > 0.05) 3.B2Panelists found 5 uM 58750445 was significantly more cooling than 0 uMWS-3 (p < 0.05) 24 and not significantly different in cooling 45 uM WS-3(p > 0.05) 3.C2 Panelists found 7 uM 59227831 was significantly morecooling than 0 uM WS-3 (p < 0.05) 32 and not significantly different incooling than 45 uM WS-3 (p > 0.05)

3.3) Preparation and Examples

Standard procedures and chemical transformation and related methods arewell known to one skilled in the art, and such methods and procedureshave been described, for example, in standard references such asFiesers' Reagents for Organic Synthesis, John Wiley and Sons, New York,N.Y., 2002; Organic Reactions, vols. 1-83, John Wiley and Sons, NewYork, N.Y., 2006; March J. and Smith M., Advanced Organic Chemistry, 6thed., John Wiley and Sons, New York, N.Y.; and Larock R. C.,Comprehensive Organic Transformations, Wiley-VCH Publishers, New York,1999. All texts and references cited herein are incorporated byreference in their entirety.

Reactions using compounds having functional groups may be performed oncompounds with functional groups that may be protected. A “protected”compound or derivatives means derivatives of a compound where one ormore reactive site or sites or functional groups are blocked withprotecting groups. Protected derivatives are useful in the preparationof the compounds of the present invention or in themselves; theprotected derivatives may be the biologically active agent. An exampleof a comprehensive text listing suitable protecting groups may be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

The example compounds were prepared according to two main schemes; thefollowing compounds were prepared according to the general proceduresoutlined in Scheme 3.1 as described herein below.

2-cyclohexyl-N-(2-(3,5-dihydroxyphenyl)-2-oxoethyl)-2-methylpropanamide.Example 3.9

2-cyclohexyl-N-(2-(3,5-dimethoxyphenyl)-2-oxoethyl)-2-methylpropanamide(1.7 mmol, 542 mg) was dissolved in dichloromethane (DCM). 1.0 M BBr₃ inDCM (2.5 mmol, 2.5 mL) was added drop wise at −78° C. The resultingmixture was allowed to warm to room temperature with stirring overnight.The reaction was quenched with H₂O (10 mL) and the aqueous layer wasextracted with DCM (50 mL×3). The organic layers were combined, washedwith brine, dried over MgSO₄ and concentrated. The resulting residue oilwas purified by preparative HPLC to give2-cyclohexyl-N-(2-(3,5-dihydroxyphenyl)-2-oxoethyl)-2-methylpropanamideas a white solid 100 mg (yield 18%). ¹H NMR (400 MHz, DMSO-d6) δ 9.618(s, 2H), 7.649 (t, J=5.2 Hz, 1H), 6.766 (s, 1H), 6.760 (s, 1H), 6.441(t, J=2 Hz, 1H), 4.350 (d, J=5.6 Hz, 2H), 1.507-1.711 (m, 6H), 0.997 (s,6H), 0.837-1.203 (m, 5H). MS 320 (MH+)

2-cyclohexyl-N-(2-(3,5-dimethoxyphenyl)-2-oxoethyl)-2-methylpropanamide.Example 3.9a

2-amino-1-(3,5-dimethoxyphenyl)ethanone hydrochloride (3.9 mmol, 900 mg)was dissolved in DCM (15 mL) and cooled to 0° C.2-cyclohexyl-2-methylpropanoyl chloride (3.9 mmol, 733 mg) was addedfollowed by the addition of triethylamine (15.6 mmol, 2.17 mL) in DCM (5mL). The resulting mixture was allowed to warm to room temperature withstirring overnight. Water was added (10 mL) and the aqueous layer wasextracted three times with DCM (50 mL×3). The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated. The resultingoil was purified by flash chromatography (Biotage 40 g silica column,0%˜40% EtOAc/Hex gradient) to afford2-cyclohexyl-N-(2-(3,5-dimethoxyphenyl)-2-oxoethyl)-2-methylpropanamideas clear oil 592 mg (yield 43%). ¹H NMR (400 MHz, DMSO-d6) δ 7.755 (t,J=5.6 Hz, 1H), 7.073 (s, 1H), 7.068 (s, 1H), 6.741 (t, J=2 Hz, 1H),4.452 (d, J=5.2 Hz, 2H), 3.786 (s, 6H), 1.502-1.700 (m, 6H), 0.992 (s,6H), 0.845-1.189 (m, 5H). MS 348 (MH+).

2-amino-1-(3,5-dimethoxyphenyl)ethanone hydrochloride. Example 3.9b

A solution of tert-butyl (2-(3,5-dimethoxyphenyl)-2-oxoethyl)carbamate(1.8 mmol, 531 mg) in EtOAc (15 mL) was cooled to 0° C. and 4.0 N HClsolution in dioxane (3.7 mmol, 0.91 mL) was added dropwise. Theresulting mixture was stirred at room temperature for 48 h andconcentrated. The product was used into the next step withoutpurification. MS 196 (MH+)

Tert-butyl (2-(3,5-dimethoxyphenyl)-2-oxoethyl)carbamate. Example 3.9c

t-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (3.0 mmol, 700mg) in dry THF (8 mL) was cooled to −15° C. and a 2.0 M solution ofisopropylmagnesium chloride in dry THF (3.0 mmol, 1.5 mL) was addeddropwise. The resulting mixture was stirred at −15° C. for 15 minutesbefore being used in the reaction described below.

1-bromo-3,5-dimethoxybenzene (3.9 mmol, 850 mg) in dry THF (10 mL) I wascooled to −78° C. and 2.5 M n-butyllithium in hexane (3.9 mmol, 1.6 mL)was added drop wise. The reaction was stirred for 5 minutes and thesolution prepared above was added drop wise by cannula at −78° C. Theresulting mixture was stirred overnight, quenched with water (5 mL) andconcentrated. Water was added (20 mL) and the mixture was extracted withEtOAc (50 mL×4). The organic layers were combined, washed with brine (50mL), dried over MgSO₄ and concentrated. The resulting oil was purifiedby flash chromatography (Biotage 40 g silica column, 0% to 30% gradientEtOAc in Hex) to give 540 mg of tert-butyl(2-(3,5-dimethoxyphenyl)-2-oxoethyl)carbamate as a colorless oil. (yield47%). MS 296 (MH+).

2-cyclohexyl-2-methyl-N-(2-oxo-2-phenylethyl)propanamide. Example 3.11

To a solution of 2-(3-hydroxyphenyl)-2-oxoethanaminium chloride (Example3.11c) (0.19 g, 1 mmol) in DCM (5 mL) was added a solution of2-cyclohexyl-2-methylpropanoyl chloride (0.19 g, 1 mmol) in DCM (2 mL)and triethylamine (0.3 mL, 2 mmol). The reaction was stirred at roomtemperature overnight then concentrated. The crude product was dissolvedin DCM and purified by flash chromatography (Silicycle XXg column, 0-20%DCM/EtOAc gradient). The material was further purified by preparativeHPLC to afford ˜50 mg of2-cyclohexyl-2-methyl-N-(2-oxo-2-phenylethyl)propanamide as a whitesolid. MS (M+H)=304. ¹H NMR (400 MHz, dmso) δ 0.85-0.97 (m, 2H), 1.01(s, 6H), 1.04-1.25 (m, 3H), 1.49-1.77 (m, 6H), 4.44 (d, J=5.5 Hz, 2H),7.01-7.04 (m, 1H), 7.28-7.30 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.42-7.44(m, 1H), 9.81 (s, 1H).

2-cyclohexyl-2-methylpropanoyl chloride. Example 3.11a

To a round bottom flask equipped with a gas bubbler was added2-cyclohexyl-2-methylpropanoic acid (Example 3.11b) (1.3 g, 7.5 mmol)and DCM (10 mL). Oxalyl chloride (1 mL, 11.3 mmol) was added followed bya few drops of DMF at room temperature. The resulting solution wasstirred at room temperature until gas evolution ceased (˜1 h). Themixture was concentrated 3 times from DCM and the resulting acidchloride was used without further purification for the coupling above.

2-cyclohexyl-2-methylpropanoic acid. Example 3.11b

2-methyl-2-phenylpropanoic acid (10 g, 61 mmol), acetic acid (60 mL) and5 wt % Rh/Al₂O₃ (2.0 g) were combined in a glass beaker. The beaker wasplaced in the stainless steel pressure reactor and the reaction mediumwas stirred under H₂ atmosphere (110 psi) overnight. The reactionmixture was filtered thru celite and washed with ethyl acetate thenconcentrated. The residue was dissolved in diethyl ether, washed withwater (50 mL×4), and brine (50 mL×2), dried over MgSO₄ and concentratedto give 2-cyclohexyl-2-methylpropanoic acid as a white solid (˜10 g, 95%yield). UPLC MS (M−H)=169; ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H),1.72 (dt, J=12.2, 2.7 Hz, 2H), 1.67-1.51 (m, 3H), 1.47 (dt, J=11.9, 3.0Hz, 1H), 1.25-1.01 (m, 3H), 1.00 (s, 6H), 0.98-0.87 (m, 2H).

2-(3-hydroxyphenyl)-2-oxoethanaminium chloride. Example 3.11c

To a 0° C. stirring solution of 2-bromo-1-(3-hydroxyphenyl)ethanone(5.00 g; 23.25 mmol) in DMF (10.0 mL) was added sodium azide (1.59 g;24.41 mmol) and the reaction was stirred overnight allowing to reachroom temperature. The reaction mixture was concentrated and suspended inethyl acetate then washed with water (20 mL), brine (20 mL) and driedover magnesium sulfate. Solvent was evaporated and the crude azide wasdissolved in a 1.25 M solution of hydrochloric acid in ethanol (30.0mL). Palladium on charcoal (500 mg of 10% dispersion) was added and thereaction was stirred overnight under Hydrogen. The mixture was filteredthrough Celite and washed with ethanol. The filtrate was evaporated anddried under vacuum to give 2.534 g of2-(3-hydroxyphenyl)-2-oxoethanaminium chloride (13.48 mmol, 58%). Thematerial was used without further purification in the next step.

2-cyclohexyl-2-methyl-N-(2-oxo-2-phenylethyl)propanamide. Example 3.12

Prepared in a similar manner as described in Example 3.9a starting from2-(3-hydroxyphenyl)-2-oxoethanaminium chloride (Example 3.11c) (2.94mmol) and 2-amino-1-phenylethanone hydrochloride (555 mg, 3.23 mmol) togive 466.5 mg of the title compound, (55%). ¹H NMR (400 MHz, DMSO-d₆) δ7.98 (d, J=8.4, 2H), 7.78 (t, J=5.5 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H),7.53 (t, J=7.6 Hz, 2H), 4.50 (d, J=5.5 Hz, 2H), 1.79-1.65 (m, 2H),1.65-1.47 (m, 4H), 1.25-1.03 (m, 3H), 1.01 (s, 6H), 0.99-0.84 (m, 2H).MS 288 (MH⁺).

2-cyclohexyl-2-methyl-N-(2-oxo-2-(pyridin-3-yl)ethyl)propanamide.Example 3.14

To a stirred solution of 2-cyclohexyl-2-methylpropanoyl chloride(Example 3.11a) (0.46 mmol, 86 mg) and 2-amino-1-(pyridin-3-yl)ethanonehydrochloride (0.46 mmol, 80 mg) in DCM (5 mL) at 0° C. was addedtriethylamine (1.4 mmol, 195 uL). The resulting mixture was stirredovernight warming to room temperature, then quenched with water andextracted with DCM (50 mL×3). The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated. The resulting oil residuewas purified by preparative HPLC to give the title compound as acolorless oil (45 mg; yield 34%). ¹H NMR (400 MHz, CDCl₃) δ 9.207 (s,1H), 8.837 (d, J=4.4 Hz, 1H), 8.242 (dt, J=8 Hz & 1.6 Hz, 1H), 7.456(dd, J=8 Hz & 5.2 Hz, 1H), 6.685 (s, 1H), 4.770 (d, J=4.4 Hz, 2H),1.591-1.777 (m, 6H), 1.180 (s, 6H), 0.965˜1.335 (m, 5H). MS 289 (MH+)

2-amino-1-(pyridin-3-yl)ethanone hydrochloride

A solution of tert-butyl (2-oxo-2-(pyridin-3-yl)ethyl)carbamate (0.46mmol, 108 mg) in EtOAc (6 mL) at 0° C. was treated with 4.0 N HCl indioxane (0.70 mmol, 174 uL). The resulting mixture was stirred at roomtemperature for 48 h and concentrated. The resulting product was usedinto the next step without further purification. MS 137 (MH+).

Tert-butyl (2-oxo-2-(pyridin-3-yl)ethyl)carbamate

To a solution of 3-bromopyridine (4.0 mmol, 627 mg) in THF (20 mL) at−78° C. was added a 2.5 M solution of n-butyllithium in hexane (4.0mmol, 1.6 mL). The reaction was stirred for 10 minutes and t-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (4.0 mmol, 932 mg) wasadded in one portion. The resulting mixture was stirred at −78° C. for30 minutes then allowed to warm to room temperature overnight. Thereaction was quenched with water (5 mL) and diluted with EtOAc (50 mL)and H₂O (20 mL). The aqueous layer was extracted with EtOAc (50 mL×3)and the combined organic layers were washed with brine (50 mL), driedover MgSO₄ and concentrated. The resulting oil was purified by flashchromatography (Biotage 40 g silica column, 20% to 50% EtOAc in Hexgradient) to give Tert-butyl (2-oxo-2-(pyridin-3-yl)ethyl)carbamate as acolorless oil 210 mg (yield 22%). ¹H NMR (400 MHz, DMSO-d6) δ 9.110 (d,J=2.4 Hz, 1H), 8.781 (dd, J=1.6 Hz & 4.8 Hz, 1H), 8.242 (dt, J=8 Hz & 2Hz, 1H), 7.538 (dd, J=8 Hz & 4.8 Hz, 1H), 7.155 (t, J=6 Hz, 1H), 4.436(d, J=5.6 Hz, 2H), 0.362 (s, 9H). MS 289 (MH+).

2-cyclohexylidene-N-methyl-N-(2-oxo-2-phenylethyl)propanamide. Example3.15

2-cyclohexylidenepropanoic acid (227 mg, 1.47 mmol, 1.0 eq) wasdissolved in DCM (25 mL) and cooled to 0° C. followed by the addition ofoxalyl chloride (0.134 mL, 1.54 mmol, 1.05 eq) and DMF (3 drops,catalytic). The mixture was stirred and allowed to warm to roomtemperature. The reaction was stirred an additional hour after gasevolution had ceased then the reaction was concentrated and re-dilutedin DCM (20 mL). 2-(methylamino)-1-phenylethanone hydrochloride salt (409mg, 2.21 mmol, 1.5 eq) was added followed by the slow addition of asolution of pyridine (0.297 mL, 3.68 mmol, 2.5 eq) in DCM (10 mL). Thereaction mixture was allowed to stir at room temperature overnight thenconcentrated. The crude mixture was partitioned between ethyl acetateand 1.0 N HCl (25 mL each). The layers were separated and the organiclayer was washed with 1.0 N NaOH (25 mL), brine (25 mL), dried oversodium sulfate and concentrated. The crude material was purified by HPLC(MeCN/water) to obtain 130 mg of the desired compound (31%). ¹H NMR (400MHz, DMSO-d6): δ, ppm: 8.05 (t, 1H, J=5.6 Hz), 7.99 (m, 2H), 7.66 (t,1H, J=6.0 Hz), 7.54 (t, 2H, J=8.0 Hz, 4.57 (d, 2H, J=5.6 Hz), 2.22 (m,2H), 2.12 (m, 2H), 1.75 (s, 3H), 1.51 (m, 6H).

2-cyclohexylidenepropanoic acid. Example 3.15a

Methyl 2-bromopropanoate (1.0 eq, 10 g, 59.9 mmol) and triethylphosphite(5.0 eq, 299.5 mmol, 51.5 mL) were combined neat and heated to 110° C.with stirring overnight. The reaction mixture was concentrated,azeotroped with toluene 3×, and dried under high vacuum. The resultingphosphonate was obtained in quantitative yield and was used directly inthe following reaction: The phosphonate (1.0 eq, 10.0 g, 44.6 mmol) wasdissolved in anhydrous THF (100 mL) and cooled to 0° C. To this mixture,n-BuLi (2.5 M in Hexanes, 18.7 mL, 46.8 mmol, 1.05 eq) was added dropwise. The mixture was stirred for 2 hours at 0° C., then cyclohexanone(1.0 eq, 44.6 mmol, 4.6 mL) was added. The mixture was stirred at 0° C.gradually warming to ambient temperature over 72 hours. The reaction wasquenched with saturated aqueous ammonium chloride (500 mL) andconcentrated. The remaining aqueous layer was extracted with ethylacetate (2×200 mL) to give 16.8 g of the crude ester as a yellow oilwhich was purified by flash column chromatography (hex/ethyl acetategradient). 3.7 g of a pale yellow oil was obtained as mixture of methyland ethyl esters in about 1.4:1 molar ratio (21.25 mmol, 48% yield). Theisolated mixed ester (3.2 g, 18.36 mmol) was dissolved in ethanol (50mL) and solid sodium hydroxide (1.0 g, 25 mmol) was added. The mixturewas refluxed until reaction was complete. Ethanol was subsequentlyremoved and the residue was partitioned between ethyl acetate (50 mL)and a 1.0 N solution of HCl (50 mL). The aqueous layer was acidifiedwith 6.0 N HCl until acidic and extracted with ethyl acetate (50 mL)again. Combined organic layers were washed with brine and dried overmagnesium sulfate. The crude material was purified by flash columnchromatography (hex/ethyl acetate gradient) to afford 2.0 g (71% yield)of the desired isomer as a yellow oil in 90% purity by ¹H-NMR.

¹H NMR (400 MHz, DMSO-d6): δ, ppm: 12.18 (s, 1H), 2.40 (m, 2H), 2.17 (m,2H), 1.77 (s, 3H), 1.52 (m, 6H).

2-cyclohexyl-N-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpropanamide.Example 3.17

To a solution of commercial 2-amino-1-(3-fluorophenyl)ethanone (0.08 g,0.5 mmol) in DCM (5.0 mL) was added a solution of2-cyclohexyl-2-methylpropanoyl chloride (Example 3.11a) (0.09 g, 0.5mmol) in DCM (2.0 mL) and triethylamine (0.15 mL, 1.0 mmol). Thereaction was stirred at room temperature overnight then concentrated.The crude product was dissolved in DCM and purified by flashchromatography (silicycle column, DCM/EtOAc gradient 0-20%) to afford2-cyclohexyl-N-(2-(3-fluorophenyl)-2-oxoethyl)-2-methylpropanamide as awhite solid. MS (M+H)=306. ¹H NMR (400 MHz, DMSO-d6): δ 7.80-7.89 (m,2H), 7.73-7.77 (ddd, J=9.8, 2.6, 1.5 Hz, 1H), 7.59 (td, J=8.0, 5.8 Hz,1H), 7.51 (tdd, J=8.4, 2.6, 1.0 Hz, 1H), 4.48 (d, J=5.4 Hz, 2H),1.49-1.75 (m, 6H), 1.02-1.24 (m, 3H), 1.00 (s, 6H), 0.84-0.99 (m, 2H),

2-cyclohexyl-N-(2-(4-fluorophenyl)-2-oxoethyl)-2-methylpropanamide.Example 3.19

Prepared in a similar manner as of Example 3.9a from2-amino-1-(4-fluorophenyl)ethanone hydrochloride (Example 3.19a) (0.32mmol, 60 mg) and 2-cyclohexyl-2-methylpropanoyl chloride (Example 3.11b)(0.32 mmol, 60 mg). The product was obtained as a white solid 40 mg(yield 41%). ¹H NMR (400 MHz, DMSO-d6) δ 8.021 (dd, J=8.4 Hz & 5.6 Hz,2H), 7.768 (t, J=5.2 Hz, 1H), 7.315 (t, J=8.8 Hz, 2H), 4.450 (d, J=5.6Hz, 2H), 1.491˜1.692 (m, 6H), 0.985 (s, 6H), 0.809˜1.176 (m, 5H). MS 306(MH+).

2-amino-1-(4-fluorophenyl)ethanone hydrochloride. Example 3.19a

Prepared in a similar manner as of Example 3.9b from tert-butyl(2-(4-fluorophenyl)-2-oxoethyl)carbamate (Example 3.19b) (0.32 mmol, 81mg). The 60 mg (quant.) of the product were obtained and used into thenext step without further purification.

Tert-butyl (2-(4-fluorophenyl)-2-oxoethyl)carbamate. Example 3.19b

Prepared in a similar manner as of Example 3.9c from t-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (2.0 mmol, 467 mg),isopropylmagnesium chloride 2.0 M in THF (2.0 mmol, 1.0 mL), and1-bromo-4-fluorobenzene (2.6 mmol, 850 mg). The final product wasobtained as a white solid 290 mg. (yield 57%). ¹H NMR (400 MHz, DMSO-d6)δ 8.025 (dd, J=9.2 Hz & 5.6 Hz, 2H), 7.327 (t, J=9.2 Hz, 1H), 7.067 (t,J=6 Hz, 2H), 4.397 (d, J=6 Hz, 2H), 1.371 (s, 9H). MS 254 (MH+)

1-cyclohexyl-N-methyl-N-(2-oxo-2-phenylethyl)cyclobutanecarboxamide.Example 3.20

To a solution of 2-(methylamino)-1-phenylethanone hydrochloride (90 mg,0.50 mmol) in DCM (5.0 mL) was added a solution of1-cyclohexylcyclobutanecarbonyl chloride (100 mg, 0.50 mmol) in DCM (2mL) and triethylamine (0.170 mL, 1 mmol). The reaction was stirred atroom temperature overnight then concentrated. The crude product wasdissolved in DCM and purified by flash chromatography (silicycle column,DCM/EtOAc gradient 0-20%) to afford1-cyclohexyl-N-methyl-N-(2-oxo-2-phenylethyl)cyclobutanecarboxamide as awhite solid. MS (M+H)=314. ¹H NMR (400 MHz, dmso) δ 7.94-8.04 (m, 2H),7.62-7.72 (m, 1H), 7.50-7.60 (m, 2H), 4.75 (s, 2H), 2.89 (s, 3H),2.31-2.40 (m, 2H), 1.91-2.30 (m, 2H), 1.53-1.84 (m, 8H), 0.95-1.35 (m,5H).

1-cyclohexylcyclobutanecarbonyl chloride. Example 3.20a

A solution of 1-cyclohexylcyclobutanecarboxylic acid (200 mg, 1.0 mmol)in DCM (5.0 mL) was treated with oxalyl chloride (0.150 mL, 1.7 mmol)followed by a few drops of DMF at room temperature. The resultingsolution was stirred at room temperature until gas evolution ceased (˜1h). The mixture was concentrated from DCM (3×10 mL) and used withoutfurther purification for the coupling above described.

1-cyclohexylcyclobutanecarboxylic acid. Example 3.20b

1-phenylcyclobutanecarboxylic acid (800 mg, 4.5 mmol), acetic acid (10mL) and 5% wt Rh/Al₂O₃ (200 mg) were added to a glass beaker and placedin the stainless steel pressure reactor under H₂ atmosphere (110 psi)for 72 hours with stirring. The reaction mixture was filtered throughcelite and washed with EtOAc then concentrated. The residue wasdissolved in ether and washed with water (50 mL×4), and brine (50 mL×2),dried over MgSO₄ and concentrated to give1-cyclohexylcyclobutanecarboxylic acid. UPLC MS (M−H)=181. ¹H NMRindicated the purity was greater than 90%.

2-cyclohexyl-2-methyl-N-(2-oxo-2-(thiophen-3-yl)ethyl)propanamide.Example 3.22

2-cyclohexyl-2-methylpropanoic acid (Example 3.11b) (17.9 g, 105 mmol)in anhydrous DCM (100 mL) was chilled to 0° C. and DMF (0.387 mL, 5.0mmol) was added followed by oxalyl chloride (9.6 mL, 110 mmol). Themixture was stirred and allowed to warm to room temperature overnight.The mixture was concentrated and redissolved in anhydrous DCM (100 mL).2-amino-1-(thiophen-3-yl)ethanone hydrochloride (17.75 g, 99.9 mmol) wasadded and cooled in an ice bath followed by the drop wise addition of asolution of triethylamine in 50 mL DCM (26.6 mL, 199.8 mmol). Thereaction was allowed to stir and warm to room temperature for 5 hours.The reaction was concentrated and partitioned between ethyl acetate (500mL) and water (500 mL). The aqueous layer was extracted with ethylacetate (200 mL) and the combined organic layers were washed with brine,dried over sodium sulfate and concentrated. Purification by flashchromatography (Hex/EtOAc gradient), produced 25.1 g of2-cyclohexyl-2-methyl-N-(2-oxo-2-(thiophen-3-yl)ethyl)propanamide as alight yellow solid. The solids were washed with hexanes and filteredafter being chilled in the freezer to afford 24.4 g of off white solid.The solids were stirred vigorously in hot hexanes and filtered at roomtemperature (3×200-250 mL) to afford 22.1 g of desired product in highpurity as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ, ppm: 8.58 (dd,1H, J₁=1.6 Hz, J₂=2.8 Hz), 7.77 (t, 1H, J=5.6 Hz), 7.65 (dd, 1H, J₁=5.2Hz, J₂=2.8 Hz)), 7.53 (dd, 1H, J₁=5.2 Hz, J₂=1.2 Hz), 4.40 (d, 2H, J=5.6Hz), 1.61 (m, 6H), 1.15 (m, 3H), 1.02 (s, 6H), 0.91 (m, 2H),

2-amino-1-(thiophen-3-yl)ethanone hydrochloride. Example 3.22a

A solution of Tert-butyl (2-oxo-2-(thiophen-3-yl)ethyl)carbamate (15.7g, 64.9 mmol) in dioxane was treated with a solution of 4.0 Mhydrochloric acid in dioxane (65 mL). The reaction mixture was stirredat room temperature overnight. The mixture was diluted with hexanes (100mL), cooled to −5° C. and filtered. The precipitate was washed withhexanes (3×25 mL) and air dried to afford 9.94 g of the desired HCl saltas an off white solid. ¹H NMR (400 MHz, DMSO-d6): δ, ppm: 6.86 (t,broad, 1H, J=6.0 Hz), 3.82 (d, 2H, J=6.4 Hz), 3.67 (s, 3H), 3.08 (s,3H), 1.38 (s, 9H).

Tert-butyl (2-oxo-2-(thiophen-3-yl)ethyl)carbamate

To flame dried magnesium turnings (9.72 g, 400 mmol) in a 500 mL roundbottom flask, anhydrous THF (150 mL) was added at room temperature undernitrogen. The mixture was cooled in an ice bath and 1,2-dibromoethane(200 mmol, 17.2 mL) was added in 3 portions 10-15 minutes apart. Themixture was allowed to stir and gradually warm to room temperature. Oncebubbling had ceased (˜3 hours), the mixture was cooled to 0° C. and3-bromothiophene (14.0 mL, 150 mmol) was added. A 2.0M solution ofn-BuLi in THF (56.0 mL, 140 mmol) was added slowly via syringe. Themixture was allowed to warm to room temperature with stirring for 2 h.In another 1.0 L flask, tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (21.8 g, 100 mmol) wasdissolved in THF (500 mL) and charged with a 2.0M solution of i-PrMgClin THF (50 mL, 100 mmol) at −40° C. This mixture was stirred untilcomplete dissolution. Upon complete dissolution, the prepared Grignardwas transferred via syringe at −40° C. The mixture was allowed to stirovernight warming to room temperature. The reaction mixture was cooledin an ice bath and quenched with 500 mL of aqueous saturated ammoniumchloride solution. Most of the organics were evaporated and theremaining mixture was extracted with ethyl acetate (2×500 mL). Thecombined organic layer was washed with brine, dried over sodium sulfateand concentrated. This crude material was purified by flashchromatography (Hex/EtOAc gradient) to give 15.7 g of Tert-butyl(2-oxo-2-(thiophen-3-yl)ethyl)carbamate as a light yellow oil thateventually solidified upon standing. ¹H NMR (400 MHz, DMSO-d6): δ, ppm:8.56 (dd, 1H, J1=1.2 Hz, J2=2.8 Hz), 7.65 (dd, 1H, J1=2.8 Hz, J2=5.2Hz), 7.52 (dd, 1H, J1=1.2 Hz, J2=5.2 Hz), 7.09 (t, 1H, J=6.0 Hz), 4.32(d, 2H, J=6.0 Hz), 1.39 (s, 9H).

The following compounds were prepared according to the generalprocedures outlined in Scheme 3.2 as described herein below.

(+)-(5)-2-cyclohexyl-N-(2-(3-hydroxyphenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.1

To a solution of(+)-(S)-2-cyclohexyl-N-(2-(3-methoxyphenyl)-2-oxoethyl)-N-methylpropanamide(Example 3.1a) (331 mg; 1.04 mmol) in 20 mL of DCM at −78° C., under N₂atmosphere was added 1.0 M BBr₃ solution in DCM (1.5 eq; 1.56 mL; 1.56mmol). The reaction mixture was slowly warmed to room temperature andstirred for 18 h; then poured into saturated NaHCO₃ (20 mL) andextracted with DCM (3×20 mL). The combined organic phases were driedover MgSO₄ and solvent was evaporated. The residue was purified bypreparative HPLC (25 minute 5-95% CH₃CN/H₂O gradient) to give thedesired compound (45 mg; 14%) as a white powder. ¹H-NMR spectrum inDMSO-d₆ indicates a mixture of rotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 9.85(s, 1H), 7.47 (ddd, J=7.8, 1.5, 1.0 Hz, 0.3H), 7.41 (ddd, J=7.7, 1.6,1.1 Hz, 0.7H), 7.38-7.31 (m, 1.3H), 7.29 (dd, J=2.5, 1.6 Hz, 0.7H), 7.07(ddd, J=8.0, 2.6, 1.0 Hz, 0.3H), 7.04 (ddd, J=8.0, 2.6, 1.0 Hz, 0.7H),5.07 (d, J=19.3 Hz, 0.3H), 4.95 (d, J=19.3 Hz, 0.3H), 4.81 (d, J=17.7Hz, 0.7H), 4.71 (d, J=17.6 Hz, 0.7H), 3.06 (s, 2H), 2.81 (s, 1H),2.70-2.58 (m, 0.7H), 2.29-2.19 (m, 0.3H), 1.82-1.30 (m, 6H), 1.47-1.35(m, 1H), 1.27-1.01 (m, 3H), 0.97 (d, J=6.8 Hz, 2H), 0.88 (d, J=6.7 Hz,1H), 1.06-0.74 (m, 1H). MS 304 (MH⁺). [α]²⁰ _(D)=+47° (EtOH, 1 mg/mL).

(+)-(S)-2-cyclohexyl-N-(2-(3-methoxyphenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.1a

To a solution of (S)-2-cyclohexylpropanoic acid (Example 3.2a) (234 mg;1.5 mmol) in anhydrous DMF (10 mL) at room temperature were added HATU(1.3 eq.; 741 mg, 1.95 mmol) and HOAt (0.6 M in DMF; 2 eq.; 5 mL, 3.0mmol). The reaction mixture was stirred for 15 min and1-(3-methoxyphenyl)-2-(methylamino)ethanone hydrochloride (Example 3.1b)(1.3 eq.; 420 mg; 1.95 mmol) and Et₃N (1.5 eq.; 312 uL, 2.25 mmol) wereadded. The reaction mixture was stirred at room temperature overnight.The reaction medium was diluted with H₂O (20 mL) and extracted withEtOAc (3×15 mL). The combined organic phases were dried over MgSO₄ andsolvent was evaporated. The residue was purified by flash chromatography(hexane/EtOAc gradient), to obtain(+)-(S)-2-cyclohexyl-N-(2-(3-methoxyphenyl)-2-oxoethyl)-N-methylpropanamideas a yellow oil (332 mg, 69%). ¹H-NMR spectrum in d⁶-DMSO indicates amixture of rotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 7.63 (ddd, J=7.6, 1.6,1.0 Hz, 0.3H), 7.57 (ddd, J=7.7, 1.6, 1.0 Hz, 0.7H), 7.54-7.41 (m, 2H),7.27 (ddd, J=8.3, 2.7, 1.0 Hz, 0.3H), 7.23 (ddd, J=8.3, 2.7, 1.0 Hz,0.7H), 5.13 (d, J=19.4 Hz, 0.3H), 5.03 (d, J=19.4 Hz, 0.3H), 4.87 (d,J=17.7 Hz, 0.7H), 4.77 (d, J=17.7 Hz, 0.7H), 3.84 (s, 1H), 3.82 (s, 2H),3.07 (s, 2H), 2.82 (s, 1H), 2.70-2.58 (m, 0.7H), 2.29-2.22 (m, 0.3H),1.81-1.49 (m, 6H), 1.49-1.29 (m, 1H), 1.28-1.01 (m, 3H), 0.97 (d, J=6.8Hz, 2H), 0.89 (d, J=6.7 Hz, 1H), 0.95-0.71 (m, 1H). MS 318 (MH⁺).

1-(3-methoxyphenyl)-2-(methylamino)ethanone hydrochloride Example 3.1b

To a solution oftert-butyl-(2-(3-methoxyphenyl)-2-oxoethyl)(methyl)carbamate (Example3.1c) (2.5 g, 9.0 mmol) in anhydrous EtOAc (20 mL) flushed with N₂ andcooled to 0° C. was added 4.0 M HCl in dioxane (4.5 eq.; 10.0 mL, 40.0mmol) and the reaction medium was stirred for 20 h gradually warming toroom temperature. The heterogeneous solution was filtered, the whitepowder was washed with cold EtOAc (2×10 mL) and dried under vacuum toobtain the 1-(3-methoxyphenyl)-2-(methylamino)ethanone as a pale yellowsolid (1.57 g, 81%). ¹H NMR (DMSO-d₆) δ: 9.38 (s, 2H), 7.58 (ddd, J=7.7,1.6, 1.1 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.48 (dd, J=2.6, 1.5 Hz, 1H),7.31 (ddd, J=8.1, 2.7, 1.1 Hz, 1H), 4.76 (s, 2H), 3.84 (s, 3H), 2.61 (s,3H). MS 180 (MH⁺).

tert-butyl-(2-(3-methoxyphenyl)-2-oxoethyl)(methyl)carbamate. Example3.1c

To a solution oftert-butyl-(2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (2.32 g, 10.0 mmol) in 20 mL of anhydrous THF under N₂atmosphere was added (3-methoxy-phenyl)magnesium bromide (1.0 M solutionin THF; 2.1 eq; 21.0 mL; 21.0 mmol) drop wise, maintaining thetemperature between 25-45° C. The reaction was stirred at roomtemperature overnight and the obtained heterogeneous solution wasquenched with saturated NH₄Cl (50 mL) and acidified with 1N HCL topH=5-6. The reaction was extracted with EtOAc (3×50 mL). The combinedorganic phases were washed with brine, dried over MgSO₄ andsolconcentrated. The residue was purified by flash chromatography usinga hexane/EtOAc gradient, to obtain the desired compound as a yellow oil(2.5 g, 89%). ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers(˜1:1). ¹H NMR (DMSO-d₆) δ: 7.56 (tt, J=7.8, 1.2 Hz, 1H), 7.50-7.43 (m,2H), 7.24 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 4.71 (s, 1H), 4.70 (s, 1H),3.82 (s, 3H), 2.86 (s, 1.5H), 2.83 (s, 1.5H), 1.41 (s, 4.5H), 1.27 (s,4.5H). MS 180 (MH⁺).

tert-Butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate.Example 3.1d

To a solution of 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (25.0g, 132.0 mmol) in 300 mL of anhydrous THF under N₂ atmosphere was addedCDI (1.2 eq; 25.7 g; 159.0 mmol) portionwise over 10 min. The reactionmixture was stirred at room temperature for 2 h andN,O-dimethylhydroxylamine hydrochloride (1.2 eq.; 15.5 g; 159 mmol) andEt₃N (1.2 eq; 22.0 mL; 159.0 mmol) were added. The resolution wasstirred overnight at room temperature. The precipitated salts werefiltered off and the filtrate was concentrated. The residue was dilutedwith H₂O (300 mL) and extracted with EtOAc (3×100 mL). Combined organicphases were washed with 10% KHSO₄ (3×50 mL), saturated NaHCO₃ (50 mL),water and brine, then dried over MgSO₄ and concentrated. This gavetert-Butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate as acolorless oil (29 g, 95%). ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 4.08 (s, 1H), 4.07 (s,1H), 3.68 (s, 1.5H), 3.66 (s, 1.5H), 3.10 (s, 1.5H), 3.09 (s, 1.5H),2.82 (s, 1.5H), 2.78 (s, 1.5H), 1.39 (s, 4.5H), 1.33 (s, 4.5H). MS 132(MH⁺).

(S)-2-Cyclohexyl-N-methyl-N-(2-oxo-2-phenylethyl)propanamide. Example3.2

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(80 mL) and (S)-2-cyclohexylpropanoic acid (Example 3.2a) (1.57 g, 10mmol). The reaction mixture was cooled to 0° C. and HATU (5.0 g, 13mmol), HOAt (2.72 g, 20 mmol), 2-(methylamino)-1-phenylethanonehydrochloride (Example 3.2b) (1.95 g, 10.5 mmol), and Et₃N (6.4 mL, 46.1mmol) were added. The reaction was stirred at room temperatureovernight, diluted with H₂O (100 mL) and extracted and EtOAc (3×100 mL).The combined organic phases were washed with an ice-cold solution of0.5% aqueous citric acid (50 mL), saturated NaHCO₃ (50 mL), water (50mL), and brine (50 mL), then dried over MgSO₄ and concentrated. Theresidue was purified by flash chromatography (hexane/EtOAc gradient), toobtain the desired compound as a yellow oil (2.83 g, 98%). ¹H-NMR inDMSO-d₆ indicates a ˜2:1 mixture of rotamers unresolved at 80° C. LCMS,¹H-NMR, ¹³C-NMR indicate a purity of greater than 98%.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.4 Hz, 0.6H), 7.97 (d, J=8.4 Hz,1.4H), 7.74-7.62 (m, 1H), 7.62-7.46 (m, 2H), 5.15 (d, J=19.3 Hz, 0.3H),5.03 (d, J=19.3 Hz, 0.3H), 4.88 (d, J=17.7 Hz, 0.7H), 4.78 (d, J=17.7Hz, 0.8H), 3.08 (s, 2H), 2.82 (s, 1H), 2.71-2.57 (m, 0.8H), 2.34-2.19(m, 0.3H), 1.81-1.50 (m, 5H), 1.50-1.29 (m, 1H), 1.29-1.02 (m, 3H), 0.97(d, J=8.0, 2H), 0.96-0.77 (m, 2H), 0.90 (d, J=4.0, 1H). MS 288 (MH⁺).Chiral analysis showed the compound was optically pure (ee>99%)

(S)-2-Cyclohexylpropanoic acid. Example 3.2(a)

(S)-2-phenylpropanoic acid (4.92 g, 3.3 mmol), glacial acetic acid (60mL) and 5% Rh/Al₂O₃ (1.0 g) were placed in a glass beaker and the beakerwas placed in a stainless steel pressure reactor under H₂ atmosphere(110 psi) for 72 h with stirring and intermittent pressurere-adjustments. The reaction medium was filtered over Celite, washedwith AcOH and EtOAc and concentrated. The resulting oil was dissolved inEt₂O and washed with H₂O (4×50 mL) and brine (2×50 mL), dried over MgSO₄and concentrated, to obtain the desired product as an off-white powder(4.85 g, 95%).

¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 2.11 (pseudo p, J=7.0 Hz,1H), 1.75-1.53 (m, 5H), 1.52-1.37 (m, 1H), 1.27-1.02 (m, 3H), 1.00-0.81(m, 2H), 0.99 (d, J=7.0 Hz, 3H). Optical rotation+0.212 (10 mg/mL EtOH,20° C.).

2-(Methylamino)-1-phenylethanone hydrochloride. Example 3.2(b)

In a round-bottom flask, tert-butyl methyl(2-oxo-2-phenylethyl)carbamate(Example 3.2c) (1.44 g, 5.76 mmol) was flushed with N₂ and diluted withEtOAc (18 mL). 4M HCl/dioxane (10 mL, 40 mmol) was added at 0° C. andthe reaction medium was stirred for 20 h warming to room temperature.The flask was then cooled to 0° C. and the heterogeneous solution wasfiltered. The white powder was washed with cold EtOAc (3×10 mL) anddried under vacuum to obtain the 2-(Methylamino)-1-phenylethanonehydrochloride as a off white powder (0.94 g, 87%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 2H), 8.00 (d, J=7.2 Hz, 2H), 7.76(t, J=7.4 Hz, 1H), 7.67-7.56 (m, 2H), 4.78 (s, 2H), 2.64 (s, 3H). MS 150(MH⁺).

Tert-butyl methyl(2-oxo-2-phenylethyl)carbamate. Example 3.2(c)

To an oven-dried, N₂-flushed round-bottom flask was added 1Mphenylmagnesium bromide in anhydrous THF (17.8 mL, 17.8 mmol). Asolution of tert-butyl methyl(2-morpholino-2-oxoethyl)carbamate (Example3.2d) (2.2 g, 8.5 mmol) in anhydrous THF (10 mL) was added drop wiseover 10 minutes and the reaction was stirred at room temperatureovernight and quenched with saturated NH₄Cl (15 mL). Water was added (10mL) and the reaction medium was extracted with EtOAc (3×25 mL). Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography(hexane/EtOAc gradient), to obtain the title compound as a white solid(1.44 g, 68%). ¹H-NMR in DMSO-d₆ indicates a ˜1:1 mixture of rotamers.¹H NMR (400 MHz, DMSO-d₆) δ 8.02-7.91 (m, 2H), 7.67 (t, J=7.4 Hz, 1H),7.61-7.50 (m, 2H), 4.72 (s, 1H), 4.71 (s, 1H), 2.86 (s, 1.5H), 2.84 (s,1.5H), 1.41 (s, 4.5H), 1.27 (s, 4.5H). MS 150 ([M-Boc+H]⁺)

Tert-butyl methyl(2-morpholino-2-oxoethyl)carbamate. Example 3.2(d)

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(100 mL) and 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (5.0 g,26.4 mmol). CDI (5.1 g, 31.5 mmol) was added in 4 portions over 10minutes and reaction was stirred for 1 h at room temperature. Morpholine(2.8 mL, 31.5 mmol) was added and the reaction was stirred overnight atroom temperature. The resulting solution was extracted with EtOAc (3×100mL) and DCM/ACN (3×100 mL). The combined organic phases were washed withice-cold 1N HCl (100 mL), water (100 mL) and brine (50 mL), the driedover MgSO₄ and concentrated, to obtain the desired compound (2.2 g, 32%)as a ˜1:1 mixture of rotamers by ¹H-NMR. ¹H NMR (400 MHz, DMSO-d₆) δ4.02 (s, 1H), 4.00 (s, 1H), 3.59-3.51 (m, 4H), 3.46-3.36 (m, 4H), 2.78(s, 1.5H), 2.75 (s, 1.5H), 1.39 (s, 4.5H), 1.33 (s, 4.5H). MS 159([M-Boc+H]⁺).

(S)-2-cyclohexyl-N-(2-(3,5-dihydroxyphenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.3

Prepared in a similar manner as described in Example 3.1 starting from(S)-2-cyclohexyl-N-(2-(3,5-dimethoxyphenyl)-2-oxoethyl)-N-methylpropanamide(Example 3.3a) (95 mg, 0.27 mmol) to obtain the title compound (28 mg,32%) as an white powder. ¹H-NMR spectrum in DMSO-d6 indicates a mixtureof rotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 9.67 (s, 2H), 6.83 (d, J=2.2 Hz,0.6H), 6.77 (d, J=2.2 Hz, 1.4H), 6.50 (t, J=2.2 Hz, 0.3H), 6.47 (t,J=2.2 Hz, 0.7H), 4.99 (d, J=19.2 Hz, 0.3H), 4.86 (d, J=19.3 Hz, 0.3H),4.73 (d, J=17.6 Hz, 0.7H), 4.64 (d, J=17.6 Hz, 0.7H), 3.04 (s, 2H), 2.79(s, 1H), 2.68-2.58 (m, 0.7H), 2.27-2.15 (m, 0.3H), 1.80-1.48 (m, 6H),1.48-1.28 (m, 1H), 1.26-0.99 (m, 3H), 0.96 (d, J=6.8 Hz, 2H), 0.87 (d,J=6.7 Hz, 1H), 0.94-0.73 (m, 1H). MS 320 (MH⁺).

(S)-2-cyclohexyl-N-(2-(3,5-dimethoxyphenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.3a

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (156 mg; 1 mmol) and1-(3,5-dimethoxyphenyl)-2-(methylamino)ethanone hydrochloride (Example3.3b) (320 mg; 1.3 mmol) to obtain the desired compound (106 mg, 30%) asa white powder. ¹H-NMR spectrum in DMSO-d6 indicates a mixture ofrotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 7.15 (d, J=2.3 Hz, 0.6H), 7.09 (d,J=2.3 Hz, 1.4H), 6.82 (t, J=2.3 Hz, 0.3H), 6.78 (t, J=2.3 Hz, 0.7H),5.11 (d, J=19.5 Hz, 0.3H), 5.01 (d, J=19.4 Hz, 0.3H), 4.85 (d, J=17.8Hz, 0.7H), 4.75 (d, J=17.8 Hz, 0.7H), 3.82 (s, 1H), 3.81 (s, 3H), 3.06(s, 3H), 2.81 (s, 1H), 2.70-2.58 (m, 0.7H), 2.29-2.19 (m, 0.3H),1.77-1.51 (m, 6H), 1.49-1.30 (m, 1H), 1.26-1.01 (m, 3H), 0.97 (d, J=6.8Hz, 2H), 0.89 (d, J=6.6 Hz, 1H), 0.87-0.72 (m, 1H). MS 348 (MH⁺).

1-(3,5-dimethoxyphenyl)-2-(methylamino)ethanone hydrochloride. Example3.3b

Prepared in a similar manner as described in Example 3.1b starting fromtert-butyl(2-(3,5-dimethoxyphenyl)-2-oxoethyl)(methyl)carbamate (3.66 g;11.86 mmol) to obtain the desired compound as a white powder (1.152 g,67%). ¹H NMR (DMSO-d₆) δ: 9.22 (s, 2H), 7.11 (d, J=2.3 Hz, 2H), 6.87 (t,J=2.3 Hz, 1H), 4.74 (s, 2H), 3.83 (s, 6H), 2.61 (s, 3H). MS 210 (MH⁺).

Tert-butyl (2-(3,5-dimethoxyphenyl)-2-oxoethyl)(methyl)carbamate.Example 3.3c

Prepared in a similar manner as described in Example 3.1c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (1.624 g, 7.0 mmol) and (3,5-dimethoxyphenyl)magnesiumbromide (0.5 M solution in THF; 29.4 mL; 14.7 mmol) to obtain thedesired compound as an colorless oil (2.1 g, 98%). ¹H-NMR spectrum inDMSO-d6 indicates a mixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 7.09(d, J=2.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.79 (t, J=2.2 Hz, 1H), 4.69(s, 1H), 4.68 (s, 1H), 3.81 (s, 6H), 2.85 (s, 1H), 2.82 (s, 2H), 1.41(s, 4.5H), 1.28 (s, 4.5H). MS 210 (MH⁺).

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(thiophen-3-yl)ethyl)propanamide.Example 3.4

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (78 mg; 0.5 mmol) and2-(methylamino)-1-(thiophen-3-yl)ethanone hydrochloride (Example 3.4a)(124 mg; 0.65 mmol) to obtain the title compound (53 mg, 36%) as anwhite powder. ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers(˜1:2). ¹H-NMR (DMSO-d₆) δ: 8.63 (dd, J=2.8, 1.3 Hz, 0.3H), 8.56 (dd,J=2.8, 1.3 Hz, 0.7H), 7.69 (dd, J=5.1, 2.8 Hz, 0.3H), 7.66 (dd, J=5.1,2.8 Hz, 0.7H), 7.57 (dd, J=5.1, 1.3 Hz, 0.3H), 7.52 (dd, J=5.1, 1.3 Hz,0.7H), 5.02 (d, J=19.3 Hz, 0.3H), 4.89 (d, J=19.3 Hz, 0.3H), 4.77 (d,J=17.6 Hz, 0.7H), 4.67 (d, J=17.6 Hz, 0.7H), 3.07 (s, 2H), 2.82 (s, 1H),2.70-2.58 (m, 0.7H), 2.32-2.20 (m, 0.3H), 1.81-1.49 (m, 6H), 1.49-1.30(m, 1H), 1.27-1.01 (m, 3H), 0.97 (d, J=6.8 Hz, 2H), 0.89 (d, J=6.7 Hz,1H), 0.95-0.71 (m, 1H). MS 294 (MH⁺).

2-(methylamino)-1-(thiophen-3-yl)ethanone hydrochloride. Example 3.4a

Prepared in a similar manner as described in Example 3.1b starting fromtert-butyl methyl(2-oxo-2-(thiophen-3-yl)ethyl)carbamate (Example 3.4b)(1.64 g; 6.45 mmol) to obtain the desired compound as a white powder(1.08 g, 87%). ¹H-NMR (DMSO-d₆) δ: 9.25 (s, 2H), 8.66 (dd, J=2.8, 1.3Hz, 1H), 7.74 (dd, J=5.1, 2.8 Hz, 1H), 7.57 (dd, J=5.1, 1.3 Hz, 1H),4.62 (s, 2H), 2.60 (s, 3H). MS 156 (MH⁺).

Tert-butyl methyl(2-oxo-2-(thiophen-3-yl)ethyl)carbamate. Example 3.4b

Prepared in a similar manner as described in Example 3.1c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (1.83 g, 7.88 mmol) and thiophen-3-ylmagnesium iodide(0.3 M solution in THF; 55 mL; 16.56 mmol) to obtain the desiredcompound as a white powder (1.64 g, 82%). ¹H-NMR spectrum in DMSO-d₆indicates a mixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 8.56 (ddd,J=2.9, 1.8, 1.2 Hz, 1H), 7.67 (dd, J=5.1, 2.8 Hz, 1H), 7.53 (td, J=4.9,1.3 Hz, 1H), 4.60 (s, 1H), 4.59 (s, 1H), 2.86 (s, 1.5H), 2.83 (s, 1.5H),1.41 (s, 4.5H), 1.27 (s, 4.5H). MS 156 (MH⁺).

(+)-(S)-2-cyclohexyl-N-(2-(4-fluorophenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.5

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (78 mg; 0.5 mmol) and1-(4-fluorophenyl)-2-(methylamino)ethanone hydrochloride (Example 3.5a)(132 mg; 0.65 mmol) to obtain the desired compound (60 mg, 40%) as awhite powder. ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers(˜1:2). ¹H NMR (DMSO-d₆) δ: 8.12 (dd, J=8.9, 5.5 Hz, 0.6H), 8.06 (dd,J=8.9, 5.5 Hz, 1.4H), 7.41 (t, J=8.9 Hz, 0.6H), 7.37 (t, J=8.9 Hz,1.4H), 5.14 (d, J=19.3 Hz, 0.3H), 5.02 (d, J=19.3 Hz, 0.3H), 4.86 (d,J=17.7 Hz, 0.7H), 4.76 (d, J=17.7 Hz, 0.7H), 3.07 (s, 2H), 2.81 (s, 1H),2.70-2.58 (m, 0.7H), 2.32-2.20 (m, 0.3H), 1.80-1.49 (m, 6H), 1.50-1.30(m, 1H), 1.25-1.00 (m, 3H), 0.97 (d, J=6.8 Hz, 2H), 0.89 (d, J=6.7 Hz,1H), 0.95-0.71 (m, 1H). MS 306 (MH⁺).

1-(4-fluorophenyl)-2-(methylamino)ethanone hydrochloride. Example 3.5a

Prepared in a similar manner as described in Example 3.1b starting fromtert-butyl (2-(4-fluorophenyl)-2-oxoethyl)(methyl)carbamate (Example3.5b) (1.42 g; 5.33 mmol) to obtain the desired compound as a whitepowder (1.03 g, 95%). ¹H NMR (DMSO-d₆) δ: 9.15 (s, 2H), 8.09 (dd, J=8.9,5.4 Hz, 2H), 7.46 (t, J=8.8 Hz, 2H), 4.76 (s, 2H), 2.62 (s, 3H). MS 168(MH⁺).

Tert-butyl (2-(4-fluorophenyl)-2-oxoethyl)(methyl)carbamate. Example3.5b

Prepared in a similar manner as described in Example 3.1c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (1.624 g, 7.0 mmol) and (4-fluorophenyl)magnesium bromide(1.0 M solution in THF; 14.7 mL; 14.7 mmol) to obtain the desiredcompound as a white powder (1.42 g, 76%). ¹H-NMR spectrum in DMSO-d₆indicates a mixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 8.06 (ddd,J=8.8, 5.5, 3.2 Hz, 2H), 7.38 (t, J=8.9 Hz, 2H), 4.71 (s, 0.8H), 4.70(s, 1.2H), 2.86 (s, 1.3H), 2.83 (s, 1.7H), 1.41 (s, 4H), 1.26 (s, 5H).MS 168 (MH⁺).

(S)-2-cyclohexyl-N-(2-(3-fluorophenyl)-2-oxoethyl)-N-methylpropanamide.Example 3.6

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (156 mg; 1 mmol) and1-(3-fluorophenyl)-2-(methylamino)ethanone hydrochloride (Example 3.6a)(265 mg; 1.3 mmol) to obtain the desired compound as a white powder (123mg, 40%). ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers(˜1:2). ¹H NMR (DMSO-d₆) δ: 7.87 (dt, J=7.7, 1.3 Hz, 0.3H), 7.86-7.80(m, 1H), 7.75 (ddd, J=9.8, 2.6, 1.5 Hz, 0.7H), 7.67-7.48 (m, 2H), 5.16(d, J=19.5 Hz, 0.3H), 5.05 (d, J=19.5 Hz, 0.3H), 4.87 (d, J=17.8 Hz,0.7H), 4.77 (d, J=17.7 Hz, 0.7H), 3.08 (s, 2H), 2.81 (s, 1H), 2.70-2.58(m, 0.7H), 2.33-2.21 (m, 0.3H), 1.82-1.49 (m, 6H), 1.49-1.30 (m, 1H),1.28-1.01 (m, 3H), 0.96 (d, J=6.8 Hz, 2H), 0.89 (d, J=6.6 Hz, 1H),0.95-0.72 (m, 1H). MS 306 (MH⁺). [α]²⁰ _(D)=+47° (EtOH, 1 mg/mL).

1-(3-fluorophenyl)-2-(methylamino)ethanone hydrochloride. Example 3.6a

Prepared in a similar manner as described in Example 3.1b starting fromtert-butyl (2-(3-fluorophenyl)-2-oxoethyl)(methyl)carbamate (Example3.6b) (1.59 g; 5.94 mmol) to obtain the title compound as a white powder(0.97 g, 80%). ¹H NMR (DMSO-d₆) δ: 9.34 (s, 2H), 7.85 (dt, J=7.5, 1.4Hz, 1H), 7.83-7.78 (m, 1H), 7.71-7.59 (m, 2H), 4.77 (s, 2H), 2.62 (s,3H). MS 168 (MH⁺).

Tert-butyl (2-(3,5-dimethoxyphenyl)-2-oxoethyl)(methyl)carbamate.Example 3.6b

Prepared in a similar manner as described in Example 3.1c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (1.624 g, 7.0 mmol) and (3-fluorophenyl)magnesium bromide(1.0 M solution in THF; 14.7 mL; 14.7 mmol) to obtain the title compoundas a colorless oil (1.59 g, 85%). ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 7.85-7.79 (m, 1H), 7.75(ddd, J=9.7, 2.6, 1.5 Hz, 1H), 7.61 (td, J=8.0, 5.6 Hz, 1H), 7.53 (tdd,J=8.4, 2.6, 1.0 Hz, 1H), 4.73 (s, 1H), 4.72 (s, 1H), 2.86 (s, 1.4H),2.83 (s, 1.6H), 1.41 (s, 4.3H), 1.27 (s, 4.7H). MS 168 (MH⁺).

2-Cyclohexyl-N-methyl-N-(2-oxo-2-phenylethyl)propanamide. Example 3.7

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(6 mL), 2-cyclohexylpropanoic acid (210 mg, 1.3 mmol), HATU (633 mg, 1.7mmol), HOAt (349 mg, 2.6 mmol), 2-(methylamino)-1-phenylethanonehydrochloride (Example 3.2b) (269 mg, 1.4 mmol) and Et₃N (0.8 mL, 5.8mmol). The reaction medium was stirred at room temperature overnight anddiluted with water (50 mL). The reaction medium was extracted with EtOAc(3×50 mL) and the combined organic phases were washed with brine, driedover MgSO₄, and concentrated. The crude product was purified bypreparative HPLC (CH₃CN/H₂O gradient) and lyophilized to obtain thedesired racemic mixture (289 mg, 75% yield) as a colorless oil. ¹H-NMRspectrum in DMSO-d₆ indicates a ˜2:1 mixture of rotamers and matchesdescription of pure (S)-enantiomer (Example 3.2).

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=7.1 Hz, 0.7H), 7.97 (d, J=7.1 Hz,1.3H), 7.73-7.64 (m, 1H), 7.60-7.51 (m, 2H), 5.15 (d, J=19.3 Hz, 0.3H),5.03 (d, J=19.3 Hz, 0.3H), 4.88 (d, J=17.7 Hz, 0.7H), 4.78 (d, J=17.7Hz, 0.7H), 3.08 (s, 2H), 2.82 (s, 1H), 2.71-2.58 (m, 0.8H), 2.30-2.20(m, 0.3H), 1.82-1.49 (m, 5H), 1.49-1.30 (m, 1H), 1.29-1.00 (m, 3H), 0.97(d, J=6.8 Hz, 2H), 0.95-0.75 (m, 2H), 0.89 (d, J=6.7 Hz, 1H). MS 288(MH⁺).

2-Cyclohexylpropanoic acid (2). Example 3.7a

In a 250 mL round bottom flask under N₂ at 0° C. was placed NaH (1408mg, 35.2 mmol) and diisopropylamine (4965 uL, 35.2 mmol) in 60 mLanhydrous THF. 2-cyclohexylacetic acid (5 g, 32.5 mmol) in 10 mLanhydrous THF was added the reaction mixture drop-wise via syringe. Thereaction mixture was stirred at 0° C. for 30 min, then heated at 42° C.for 15 min. The mixture was then cooled to −20° C. and 1.6 Mbutyllithium in hexane (24.2 mL, 38.72 mmol) was added dropwise. Thereaction mixture was warmed to 0° C. and stirred for 15 min, then heatedat 35° C. for 30 min and a yellowish solution was obtained. The solutionwas cooled again to 0° C. and MeI (2.2 mL, 35.2 mmol) was added dropwise over 20 minutes. The reaction mixture was stirred at 0° C. for 30min, then heated at 35° C. for 1 h, and left stirring at roomtemperature overnight. The reaction mixture was diluted with H₂O (100mL) and extracted with ether (3×30 mL). The aqueous phase was acidifiedwith 6N HCl to pH=1 and extracted with EtOAc (3×60 mL). The combinedorganic fractions were washed with brine (100 mL), dried over MgSO₄ andconcentrated under vacuum. The obtained crude yellow solid (4.8 g,87.5%) was 90% clean by ¹H-NMR analysis and was used in the next stepwithout further purification. ¹H NMR (DMSO-d₆) δ: 11.97 (s, 1H), 2.10(pseudo p, J=6.9 Hz, 1H), 1.74-1.53 (m, 6H), 1.50-1.41 (m, 1H),1.27-1.02 (m, 2H), 0.99 (d, J=7.0 Hz, 3H), 0.95-0.85 (m, 2H).

3-cyclohexyl-3-methyl-1-(2-oxo-2-phenylethyl)pyrrolidin-2-one. Example3.8

To a suspension of NaH (60% in mineral oil; 78 mg; 1.95 mmol) in 10 mLof anhydrous DMF was added a solution of3-cyclohexyl-3-methylpyrrolidin-2-one (Example 3.8a) (235 mg; 1.3 mmol)in 5 mL of anhydrous DMF dropwise. The reaction mixture was stirred atroom temperature for 30 min and a solution of bromoacetophenone (310 mg;1.56 mmol) in 5 mL of DMF was added dropwise. The reaction medium wasstirred at room temperature for 18 h and then was diluted with H₂O (30mL) and extracted with EtOAc (3×20 mL). The combined organic phases werewashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by preparative HPLC (25 minutes 5-95% CH₃CN/H₂O), to give thedesired compound (24 mg; 6%) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ 0.81-1.05 (m, 2H), 1.07 (s, 3H), 1.09-1.25 (m, 2H), 1.42 (tt,J=12.0, 3.2 Hz, 1H), 1.48-1.65 (m, 2H), 1.63-1.81 (m, 5H), 1.98-2.10 (m,1H), 3.20-3.29 (m, 1H), 4.07-4.18 (m, 1H), 4.71 (d, J=17.9 Hz, 1H), 4.77(d, J=18.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 1H), 7.99(dd, J=8.4, 1.3 Hz, 2H). MS 300 (MH⁺).

3-cyclohexyl-3-methylpyrrolidin-2-one. Example 3.8a

A solution of ethyl 3-cyano-2-cyclohexyl-2-methylpropanoate (Example3.8b) (2.5 g; 11.2 mmol) and CoCl₂ ^(x)6H₂O (1.33 g; 5.6 mmol) in 60 mLof THF/H₂O (2:1) was stirred under N₂ and cooled to 0° C. To thisreaction, NaBH₄ (2.13 g; 56 mmol) was added portion wise. The resultingmixture was stirred at room temperature for 72 h then quenched withaqueous 28% NH₄OH (5 mL). The precipitated inorganic materials werefiltered off trough Celite, which was washed with a THF/H₂O mixture. Thefiltrate was concentrated under vacuum and the residue was extractedwith DCM (3×50 mL). The combined organic phases were washed with brine,dried over MgSO₄ and concentrated. The crude material was purified byflash chromatography (DCM/MeOH gradient), to obtain the desired compoundas a light green powder (465 mg, 23%). ¹H NMR (DMSO-d₆) δ: 0.77-0.92 (m,1H), 0.97 (s, 3H), 0.99-1.27 (m, 3H), 1.34 (tt, J=11.8, 3.1 Hz, 1H),1.44-1.51 (m, 1H), 1.51-1.83 (m, 6H), 1.93-2.04 (m, 1H), 3.02-3.16 (m,2H), 7.45 (s, 1H). MS 182 (MH⁺).

Ethyl 3-cyano-2-cyclohexyl-2-methylpropanoate. Example 3.8b

A solution of diisopropylamine (3.4 mL; 24 mmol) in anhydrous THF wasstirred under N₂ and cooled to −78° C. n-Butyllithium (2.5 M in hexane;9.6 mL; 24 mmol) was added drop wise and the reaction was stirred 30minutes, then a solution of ethyl 2-cyclohexylpropanoate (Example 3.8c)(4.05 g; 22 mmol) in 5 mL anhydrous THF was added drop wise. Thereaction mixture was stirred at −78° C. for 1 h, then a solution ofbromoacetonitrile (1.76 mL; 26.4 mmol) in 10 mL of anhydrous THF wasadded slowly over 30 min Stirring was continued overnight while thereaction was allowed to warm to room temperature. The reaction wasquenched with 1N HCl (100 mL) and extracted with ether (3×50 mL). thecombined organic phases were washed with saturated NaHCO₃ (100 mL),brine (50 mL), dried over MgSO₄ and concentrated. The residue waspurified on silica gel using Hexane/EtOAc gradient to afford Ethyl3-cyano-2-cyclohexyl-2-methylpropanoate as a colorless oil (2.51 g,51%). ¹H NMR (DMSO-d₆) δ: 0.89-1.17 (m, 5H), 1.18 (s, 3H), 1.20 (t,J=7.1 Hz, 3H), 1.49-1.65 (m, 4H), 1.67-1.77 (m, 2H), 2.68 (d, J=16.7 Hz,1H), 2.77 (d, J=16.7 Hz, 1H), 4.04-4.21 (m, 2H). MS 224 (MH⁺).

Ethyl 2-cyclohexylpropanoate. Example 3.8c

LiHMDS (1M in THF; 58 mL; 58 mmol) was added drop wise to a stirredsolution of ethyl 2-cyclohexylacetate (9 mL; 50 mmol) in anhydrous THF(20 mL), at −78° C. The mixture was stirred at −78° C. for 1 h then MeI(3.75 mL; 60.0 mmol) was added. The mixture was allowed to graduallywarm to room temperature, stirred an additional 18 h, then quenched withH₂O (100 mL) and extracted with EtOAc (3×50 mL). The combined organicphases were washed with brine, dried over MgSO₄ and concentrated. Theresidue was purified on silica gel using Hexane/EtOAc gradient to obtainethyl 2-cyclohexylpropanoate as a colorless oil (8.75 g, 95%). ¹H NMR(DMSO-d₆) δ: 0.83-1.00 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 1.05-1.25 (m,2H), 1.17 (t, J=7.1 Hz, 3H), 1.40-1.51 (m, 1H), 1.51-1.74 (m, 6H), 2.19(pseudo p, J=7.1 Hz, 1H), 3.97-4.11 (m, 2H). MS 185 (MH⁺).

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(thiophen-2-yl)ethyl)propanamide.Example 10

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (78 mg; 0.5 mmol) and2-(methylamino)-1-(thiophen-2-yl)ethanone hydrochloride (Example 3.6a)(124 mg; 0.65 mmol) to obtain the desired compound (146 mg, 93%) as awhite powder. ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers(˜1:2). ¹H NMR (DMSO-d₆) δ: 8.13-8.06 (m, 0.6H), 8.06-8.01 (m, 1.4H),7.31 (dd, J=4.9, 3.8 Hz, 0.3H), 7.27 (dd, J=4.9, 3.8 Hz, 0.7H), 5.07 (d,J=19.1 Hz, 0.3H), 4.95 (d, J=19.1 Hz, 0.3H), 4.81 (d, J=17.5 Hz, 0.7H),4.72 (d, J=17.5 Hz, 0.7H), 3.08 (s, 2H), 2.82 (s, 1H), 2.70-2.58 (m,0.7H), 2.34-2.24 (m, 0.3H), 1.82-1.48 (m, 6H), 1.48-1.30 (m, 1H),1.26-1.01 (m, 3H), 0.97 (d, J=6.8 Hz, 2H), 0.90 (d, J=6.7 Hz, 1H),0.95-0.73 (m, 1H). MS 294 (MH⁺).

2-(methylamino)-1-(thiophen-2-yl)ethanone hydrochloride. Example 3.10a

Prepared in a similar manner as described in Example 3.1b starting fromtert-butyl methyl(2-oxo-2-(thiophen-2-yl)ethyl)carbamate (Example 3.6b)(1.64 g; 6.45 mmol) to obtain the desired compound as a white powder(1.04 g, 84%). ¹H NMR (DMSO-d₆) δ: 9.28 (s, 2H), 8.19 (dd, J=4.9, 1.1Hz, 1H), 8.07 (dd, J=3.9, 1.1 Hz, 1H), 7.34 (dd, J=4.9, 3.9 Hz, 1H),4.68 (s, 2H), 2.61 (s, 3H). MS 156 (MH⁺).

Tert-butyl methyl(2-oxo-2-(thiophen-2-yl)ethyl)carbamate. Example 3.10b

Prepared in a similar manner as described in Example 3.1c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.1d) (1.62 g, 7.0 mmol) and thiophen-2-ylmagnesium bromide(1.0 M solution in THF; 14.7 mL; 14.7 mmol) to obtain the desiredcompound as a light-brown oil (1.64 g, 92%). ¹H-NMR spectrum in DMSO-d₆indicates a mixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 8.05 (dd,J=4.9, 1.1 Hz, 1H), 8.01 (ddd, J=5.8, 3.8, 1.1 Hz, 1H), 7.27 (ddd,J=4.8, 3.9, 0.6 Hz, 1H), 4.65 (s, 1H), 4.63 (s, 1H), 2.87 (s, 1.5H),2.84 (s, 1.5H), 1.41 (s, 4.5H), 1.26 (s, 4.5H). MS 156 (MH⁺).

N-Methyl-2-(4-methylcyclohexyl)-N-(2-oxo-2-phenylethyl)propanamide.Example 3.13

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(12 mL) and 2-(4-methylcyclohexyl)propanoic acid (Example 3.13a) (237.1mg, 1.39 mmol). The reaction was cooled to 0° C. and HATU (722 mg, 1.90mmol), HOAt (397 mg, 2.92 mmol), 2-(methylamino)-1-phenylethanonehydrochloride (Example 3.2b) (347 mg, 1.87 mmol), and NEt₃ (900 uL, 6.49mmol) were added. The reaction medium was stirred at room temperatureovernight, then diluted with H₂O (20 mL) and extracted with EtOAc (3×25mL). the combined organic phases were washed with brine (30 mL), driedover MgSO₄ and concentrated. The obtained mixture of 4 stereoisomers waspurified and separated as follows: a preparative HPLC using a CH₃CN/H₂Ogradient followed by lyophilization returned two fractions FI and FII,which were the two expected pairs of cis and trans diastereomers. Thetwo pairs of enantiomers were further resolved on a chiral column intothe single components cis-R, cis-S, trans-R and trans-S (for all ofthem: MS 302 (MH⁺)).

FI: ¹H NMR spectrum in d⁶-DMSO indicates a ˜1:2-1:3 mixture of rotamers.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.0 Hz, 0.5H), 7.97 (d, J=7.1 Hz,1.3H), 7.72-7.65 (m, 1H), 7.61-7.51 (m, 2H), 5.15 (d, J=19.2 Hz, 0.3H),5.09 (d, J=19.3 Hz, 0.3H), 4.89 (d, J=17.7 Hz, 0.7H), 4.79 (d, J=17.7Hz, 0.7H), 3.11 (s, 2H), 2.89-2.81 (m, 0.6H), 2.83 (s, 1H), 2.49-2.39(m, 0.3H), 1.74-1.50 (m, 2H), 1.50-1.12 (m, 7H), 0.98 (d, J=6.8 Hz, 2H),0.92 (d, J=6.9 Hz, 2H), 0.89 (d, J=6.7 Hz, 1H), 0.81 (d, J=7.0 Hz, 1H).MS 302 (MH⁺).

FII: ¹H NMR spectrum in d⁶-DMSO indicates a ˜1:2 mixture of rotamers.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=7.1 Hz, 0.5H), 7.97 (d, J=7.1 Hz,1.3H), 7.72-7.64 (m, 1H), 7.60-7.51 (m, 2H), 5.15 (d, J=19.3 Hz, 0.3H),5.02 (d, J=19.4 Hz, 0.3H), 4.87 (d, J=17.6 Hz, 0.7H), 4.79 (d, J=17.6Hz, 0.7H), 3.07 (s, 2H), 2.82 (s, 1H), 2.68-2.57 (m, 0.8H), 2.29-2.19(m, 0.3H), 1.83-1.49 (m, 4H), 1.48-1.12 (m, 3H), 1.05-0.99 (m, 0.7H),0.97 (d, J=6.8 Hz, 2H), 0.95-0.91 (m, 0.7H), 0.89 (d, J=6.7 Hz, 1H),0.88-0.86 (m, 0.4H), 0.85 (d, J=6.5 Hz, 2H), 0.82 (d, J=6.5 Hz, 1H),0.80 (d, J=2.7 Hz, 0.3H). MS 302 (MH⁺).

2-(4-Methylcyclohexyl)propanoic acid. Example 3.13a

Prepared in a similar fashion as described in Example 3.2a from2-(p-tolyl)propanoic acid (1.02 g, 6.23 mmol), glacial acetic acid (60mL), and 5% wt Rh/Al₂O₃ (500 mg), under H₂ pressure for 24 h, to obtainthe desired product as an off-white powder (992 mg, 94%). ¹H-NMRspectrum in DMSO-d₆ indicates an approximate 1.4:1.0 trans/cisdiastereomeric mixture. ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s, 1H), 2.28(dq, J=8.6, 7.0 Hz, 0.7H), 2.10 (pseudo p, J=7.0 Hz, 0.5H), 1.70-1.61(m, 1.8H), 1.61-1.55 (m, 0.5H), 1.51 (dq, J=7.4, 4.1 Hz, 0.7H),1.48-1.41 (m, 1H), 1.41-1.37 (m, 1.8H), 1.37-1.33 (m, 1.1H), 1.33-1.20(m, 1.8H), 1.07-1.02 (m, 0.4H), 1.01 (d, J=7.2 Hz, 1.45H), 0.99 (d,J=6.8 Hz, 1.45H), 0.98-0.95 (m, 0.3H), 0.94-0.90 (m, 0.5H), 0.88 (d,J=6.9 Hz, 1.9H), 0.84 (d, J=6.5 Hz, 1.4H).

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)propanamide.Example 3.16

A 1.0 M solution of TBAF in THF (0.300 mL, 0.300 mmol) was added to astirred solution of(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1-tosyl-1H-pyrrol-2-yl)ethyl)propanamide(Example 3.16) (127 mg, 0.300 mmol) in THF (3.0 mL) and stirring wascontinued overnight. Water (0.100 mL) was added and stirring continuedfor 5 minutes. All the volatiles were evaporated and the obtained crudewas purified by column chromatography (Hex/EtOAc gradient). In this way,47 mg (57%) of(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)propanamidewere obtained. ¹H-NMR spectrum in DMSO-d₆ indicates a mixture ofrotamers (˜1:2). ¹H NMR (DMSO-d₆) δ 11.99 (br s, 0.3H), 11.87 (br s,0.7H), 7.14-7.12 (m, 0.7H), 7.10-7.08 (m, 0.7H), 7.03-7.02 (m, 0.7H),6.24-6.22 (m, 0.3H), 6.21-6.19 (m, 0.7H), 4.76 (d, J=18.8 Hz, 0.3H),4.70 (d, J=18.8 Hz, 0.3H), 4.67 (d, J=17.2 Hz, 0.7H), 4.49 (d, J=17.2Hz, 0.7H), 3.06 (s, 2H), 2.82 (s, 1H), 2.70-2.58 (m, 0.7H), 2.30-2.21(m, 0.3H), 1.83-1.49 (m, 5H), 1.48-1.28 (m, 1H), 1.26-1.03 (m, 3H),1.02-0.77 (m, 5H),

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1-tosyl-1H-pyrrol-2-yl)ethyl)propanamide.Example 3.16a

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (156 mg; 1.0 mmol) and2-(methylamino)-1-(1-tosyl-1H-pyrrol-2-yl)ethanone hydrochloride(Example 3.16b) (427 mg; 1.3 mmol) to obtain the desired compound (250mg, 58%) as a white powder. ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 7.96 (dd, J=3.2, 1.6 Hz,0.3H), 7.91 (dd, J=3.2, 1.7 Hz, 0.7H), 7.87 (t, J=8.4 Hz, 2H), 7.55 (dd,J=3.9, 1.7 Hz, 0.3H), 7.47 (dd, J=3.8, 1.7 Hz, 0.7H), 7.42 (td, J=8.7,0.6 Hz, 2H), 6.56 (dd, J=3.8, 3.2 Hz, 0.3H), 6.50 (dd, J=3.8, 3.2 Hz,0.7H), 4.79 (d, J=19.1 Hz, 0.3H), 4.73 (d, J=19.1 Hz, 0.3H), 4.64 (d,J=17.3 Hz, 0.7H), 4.44 (d, J=17.2 Hz, 0.7H), 2.96 (s, 2H), 2.72 (s, 1H),2.64-2.54 (m, 0.7H), 2.38 (s, 2H), 2.37 (s, 1H), 2.10-1.98 (m, 0.3H),1.76-1.48 (m, 6H), 1.46-0.93 (m, 4H), 0.91 (d, J=6.8 Hz, 2H), 0.76 (d,J=6.7 Hz, 1H), 0.96-0.62 (m, 1H). MS 431 (MH⁺).

2-(methylamino)-1-(1-tosyl-1H-pyrrol-2-yl)ethanone hydrochloride.Example 3.16b

Prepared in a similar manner as described in Example 3.2b starting fromtert-butyl methyl(2-oxo-2-(1-tosyl-1H-pyrrol-2-yl)ethyl)carbamate(Example 3.16c) (1.24 g; 3.15 mmol) to obtain the desired compound (0.58g, 56%) as a white powder. ¹H NMR (DMSO-d₆) δ: 8.91 (s, 2H), 8.07 (dd,J=3.2, 1.7 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.56 (dd, J=3.9, 1.7 Hz,1H), 7.48 (dd, J=8.6, 0.8 Hz, 2H), 6.62 (dd, J=3.9, 3.2 Hz, 1H), 4.49(s, 2H), 2.51 (s, 3H), 2.41 (s, 3H). MS 293 (MH⁺).

Tert-butyl methyl(2-oxo-2-(1-tosyl-1H-pyrrol-2-yl)ethyl)carbamate.Example 3.16c

To a solution of 2-bromo-1-tosyl-1H-pyrrole (4.0 g, 13.3 mmol) in 10 mLof anhydrous THF under N₂ atmosphere at 0° C. was addedi-propylmagnesium chloride, lithium chloride complex (1.3 M solution inTHF; 11.3 mL; 14.7 mmol) over 10 minutes. The reaction medium wasstirred at 0° C. for 1 h, then added to the solution of tert-butyl(2-(methoxy-(methyl)amino)-2-oxoethyl)(methyl)carbamate (Example 3.2d)(1.5 g, 6.3 mmol) in 20 mL of anhydrous THF over 10 minutes maintainingthe temperature between 25-45° C. The reaction was stirred at roomtemperature overnight and the obtained heterogeneous solution wasquenched with saturated NH₄Cl (50 mL) and acidified with 1 N HCl topH=5-6. The reaction medium was extracted with EtOAc (3×50 mL). Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated. The residue was purified on silica gel using ahexane/EtOAc gradient, to obtain the desired title compound as anorange-yellow oil (1.24 g, 23%). ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜2:1). ¹H NMR (DMSO-d₆) δ: 7.93 (m, 1H), 7.84 (m,2H), 7.48-7.39 (m, 2.4H), 7.34 (dd, J=3.3, 1.8 Hz, 0.6H), 6.24-6.19 (m,1H), 4.43 (s, 0.6H), 4.39 (s, 1.4H), 2.74 (s, 1H), 2.73 (s, 2H), 2.37(s, 3H), 1.37 (s, 3H), 1.12 (s, 6H). MS 293 (MH⁺).

N-Methyl-2-(3-methylcyclohexyl)-N-(2-oxo-2-phenylethyl)propanamide.Example 3.18

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(6.0 mL) and 2-(3-methylcyclohexyl)propanoic acid (Example 3.18a) (134mg, 0.79 mmol). The solution was cooled to 0° C. and HATU (389 mg, 1.02mmol), HOAt (214 mg, 1.57 mmol), 2-(methylamino)-1-phenylethanonehydrochloride (Example 3.2b) (161 mg, 0.87 mmol), and NEt₃ (491 uL, 3.54mmol) were added. The reaction medium was stirred at room temperatureovernight, then diluted with H₂O (10 mL) and extracted with EtOAc (3×10mL). The combined organic phases were washed with brine (15 mL), driedover MgSO₄ and concentrated. The obtained residue was purified bypreparative HPLC using a CH₃CN/H₂O gradient and lyophilized to give thedesired mixture of 8 stereoisomers (112 mg, 47%). Further separation ona chiral column only allowed to isolate 3 fractions F1, F2, F3 (302(MH⁺)).

¹H-NMR spectrum in DMSO-d₆ indicates a mixture of 4 diastereomericpairs, 3 of which may appear as a mixture of rotamers (˜1:1) based onthe NMe signals.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.3 Hz, 0.6H), 7.97 (d, J=8.4 Hz,1.3H), 7.73-7.64 (m, 1H), 7.60-7.51 (m, 2H), 5.21-4.74 (m, 2H), 3.17 (s,0.1H), 3.16 (s, 0.1H), 3.10 (s, 0.2H), 3.09 (s, 0.2H), 3.07 (s, 1.6H),2.83 (s, 0.4H), 2.82 (s, 0.4H), 2.68-2.58 (m, 0.6H), 2.34-2.21 (m,0.3H), 1.82-1.57 (m, 4H), 1.57-1.36 (m, 2H), 1.36-1.07 (m, 2H),0.99-0.94 (m, 2H), 0.92-0.80 (m, 4H), 0.79-0.72 (m, 1H), 0.71-0.41 (m,1H). MS 302 (MH⁺).

2-(3-Methylcyclohexyl)propanoic acid. Example 3.18a

Prepared in a similar fashion as described in Example 3.2a from2-(m-tolyl)propanoic acid (0.5 g, 3.05 mmol), glacial acetic acid (40mL) and 5% wt Rh/Al₂O₃ (483 mg), under H₂ pressure for 24 h, to obtainthe desired product as an off-white powder (442 mg, 85%). ¹H-NMRspectrum in DMSO-d₆ indicates a mixture of diastereoisomers, ¹H NMR (400MHz, DMSO-d₆) δ 11.99 (s, 1H), 2.30-2.19 (m, 0.3H), 2.10 (td, J=7.0, 5.5Hz, 0.9H), 1.73-1.64 (m, 1.4H), 1.64-1.56 (m, 2H), 1.56-1.52 (m, 0.5H),1.52-1.42 (m, 1.4H), 1.42-1.27 (m, 1.3H), 1.26-1.15 (m, 1.4H), 1.01-0.98(m, 2.9H), 0.94-0.90 (m, 0.3H), 0.90-0.83 (m, 3.3H), 0.77 (td, J=12.1,3.5 Hz, 0.9H), 0.72-0.53 (m, 0.8H).

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(pyridin-3-yl)ethyl)propanamide.Example 3.21

Prepared in a similar manner as described in Example 3.1a starting from(S)-2-cyclohexylpropanoic acid (0.25 mmol, 39 mg) to obtain 15 mg of thedesired compound as a clear oil (yield 21%). ¹H NMR (400 MHz, CDCl₃) δ9.167 (d, J=2 Hz, 1H), 8.789 (dd, J=2 Hz & 4.8 Hz, 1H), 8.233 (dt, J=8Hz & 4.8 Hz, 1H), 7.412 (dd, J=8 Hz & 4.8 Hz, 1H), 4.834 (d, J=17.2,1H), 4.743 (d, J=17.2, 1H), 3.169 (s, 3H), 2.565 (m, 1H), 1.566˜1.870(m, 7H), 1.108 (s, 3H), 0.868˜1.301 (m, 4H). MS 289 (MH+).

2-(methylamino)-1-(pyridin-3-yl)ethanone hydrochloride. Example 3.21a

Prepared in a similar manner as described in Example 3.9b starting fromtert-butyl methyl(2-oxo-2-(pyridin-3-yl)ethyl)carbamate (0.40 mmol, 100mg), 4.0 N HCl in dioxane (2.70 mmol, 0.675 mL) and EtOAc (6.0 mL) toobtain 55 mg of the desired compound as yellow solids (yield 72%). MS151 (MH+).

Tert-butyl methyl(2-oxo-2-(pyridin-3-yl)ethyl)carbamate. Example 3.21b

Prepared in a similar manner as described in Example 3.9c starting from3-bromopyridine (2.0 mmol, 316 mg) and tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate (2.0 mmol, 464mg) to obtain 200 mg of the desired compound as a clear oil (yield 40%).MS 251 (MH+).

N-Methyl-2-(2-methylcyclohexyl)-N-(2-oxo-2-phenylethyl)propanamide.Example 3.23

To an oven-dried, N₂-flushed round-bottom flask were added anhydrous DMF(6.0 mL) and 2-(2-methylcyclohexyl)propanoic acid (Example 3.23a) (113mg, 0.66 mmol). The solution was cooled to 0° C. and HATU (328 mg, 0.86mmol), HOAt (181 mg, 1.33 mmol), 2-(methylamino)-1-phenylethanonehydrochloride (Example 3.2b) (186 mg, 1.00 mmol), and Et₃N (620 uL, 4.47mmol) were added. The reaction mixture was stirred at room temperatureovernight then diluted with H₂O (10 mL) and extracted with EtOAc (3×15mL). the combined organic phases were washed with brine (10 mL), driedover MgSO₄ and concentrated. The obtained residue was purified bypreparative HPLC using a CH₃CN/H₂O gradient and lyophilized to affordthe desired mixture of diastereoisomers (65 mg, 32%). Further separationon a chiral column only allowed to isolate 3 fractions F1, F2, F3 (MS302 (MO). ¹H-NMR spectrum in DMSO-d₆ indicates a mixture of 3 majordiastereomeric pairs. ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=7.1 Hz,0.4H), 7.97 (d, J=7.1 Hz, 1.6H), 7.72-7.64 (m, 1H), 7.60-7.51 (m, 2H),5.11 (d, J=20.0 Hz, 0.2H), 5.05 (d, J=20.0 Hz, 0.2H), 4.89 (d, J=20.0Hz, 0.7H), 4.86 (d, J=16.0 Hz, 0.1H), 4.80 (d, J=16.0 Hz, 0.1H), 4.80(d, J=20.0 Hz, 0.7H), 3.10 (s, 0.3H), 3.08 (s, 2.0H), 2.83 (s, 0.7H),2.70-2.59 (m, 1H), 2.25-2.16 (m, 0.3H), 2.03-1.93 (m, 0.8H), 1.93-1.85(m, 0.3H), 1.64-1.51 (m, 3H), 1.50-1.29 (m, 4H), 1.27-1.02 (m, 2H), 1.00(d, J=6.8 Hz, 0.3H), 0.96 (d, J=6.7 Hz, 2H), 0.87 (d, J=4.0 Hz, 2H),0.87 (d, J=4.0 Hz, 0.6H), 0.83 (d, J=7.2 Hz, 0.3H), 0.68 (d, J=7.1 Hz,0.6H). MS 302 (MH⁺).

2-(2-Methylcyclohexyl)propanoic acid. Example 3.23a

Prepared in a similar fashion as described in Example 3.2a from2-(o-tolyl)propanoic acid (543 mg, 3.31 mmol), glacial acetic acid (40mL) and 5% wt Rh/Al₂O₃ (474 mg), to obtain the desired product under H₂pressure for 24 h, as an off-white powder (481 mg, 85%). ¹H-NMR spectrumin DMSO-d₆ indicates a mixture of diastereoisomers, showing one majorset of signals and two less prevalent ones. ¹H NMR (400 MHz, DMSO-d₆) δ12.01 (s, 1H), 2.11-2.05 (m, 0.2H), 2.05-1.99 (m, 0.8H), 1.98-1.91 (m,0.9H), 1.69-1.58 (m, 1.1H), 1.58-1.49 (m, 1.3H), 1.49-1.39 (m, 1.9H),1.39-1.32 (m, 1.8H), 1.32-1.25 (m, 1.2H), 1.21-1.09 (m, 2H), 1.03 (d,J=6.9 Hz, 0.4H), 1.00 (d, J=6.9 Hz, 2.5H), 0.89-0.81 (m, 0.6H), 0.78 (d,J=7.1 Hz, 2.5H).

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1H-pyrrol-3-yl)ethyl)propanamide.Example 3.24

Prepared in a similar manner as described in Example 3.16 from(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1-tosyl-1H-pyrrol-3-yl)ethyl)propanamide(Example 3.24a) (94 mg, 0.2256 mmol) to give 28 mg (45% yield) of thedesired product(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1H-pyrrol-3-yl)ethyl)propanamide.¹H-NMR spectrum in DMSO-d₆ indicates a mixture of rotamers (˜1:1.5). ¹HNMR (DMSO-d₆) δ 11.57 (br s, 0.4H), 11.43 (br s, 0.6H), 7.72 (br s,0.4H), 7.63 (br s, 0.6H), 6.88 (br s, 0.4H), 6.85 (br s, 0.6H), 6.51 (brs, 0.4H), 6.46 (br s, 0.6H), 4.78 (d, J=19.0 Hz, 0.4H), 4.64 (d, J=19.0Hz, 0.4H), 4.60 (d, J=17.0 Hz, 0.6H), 4.50 (d, J=17.0 Hz, 0.6H), 3.03(br s, 1.8H), 2.80 (br s, 1.2H), 2.68-2.58 (m, 0.6H), 2.27-2.17 (m,0.4H), 1.88-0.72 (m, 14H)

(S)-2-cyclohexyl-N-methyl-N-(2-oxo-2-(1-tosyl-1H-pyrrol-3-yl)ethyl)propanamide.Example 3.24a

Prepared in a similar manner as described in Example 3.2a starting from(S)-2-cyclohexylpropanoic acid (156 mg; 1.0 mmol) and2-(methylamino)-1-(1-tosyl-1H-pyrrol-3-yl)ethanone hydrochloride(Example 3.24b) (427 mg; 1.3 mmol) to obtain the desired compound (181mg, 42%) as an white powder. ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜1:2). ¹H NMR (DMSO-d₆) δ: 8.35 (dd, J=2.1, 1.6 Hz,0.3H), 8.25 (dd, J=2.1, 1.6 Hz, 0.7H), 7.97 (d, J=8.4 Hz, 2H), 7.53-7.47(m, 2.3H), 7.46 (dd, J=3.3, 2.1 Hz, 0.7H), 6.72 (dd, J=3.3, 1.6 Hz,0.3H), 6.67 (dd, J=3.3, 1.6 Hz, 0.7H), 4.89 (d, J=19.2 Hz, 0.3H), 4.79(d, J=19.3 Hz, 0.3H), 4.64 (d, J=17.6 Hz, 0.7H), 4.53 (d, J=17.6 Hz,0.7H), 3.02 (s, 2H), 2.77 (s, 1H), 2.65-2.56 (m, 0.7H), 2.40 (s, 3H),2.29-2.17 (m, 0.3H), 1.92-1.45 (m, 6H), 1.45-1.23 (m, 1H), 1.23-1.01 (m,3H), 0.94 (d, J=6.8 Hz, 2H), 0.86 (d, J=6.7 Hz, 1H), 0.95-0.70 (m, 1H).MS 431 (MH⁺).

2-(methylamino)-1-(1-tosyl-1H-pyrrol-3-yl)ethanone hydrochloride.Example 3.24b

Prepared in a similar manner as described in Example 3.2b starting fromtert-butyl methyl(2-oxo-2-(1-tosyl-1H-pyrrol-3-yl)ethyl)carbamate(Example 3.24c) (1.1 g; 2.8 mmol) to obtain the desired compound (0.58g, 56%) as a white powder. ¹H NMR (DMSO-d₆) δ: 9.16 (s, 2H), 8.39 (d,J=1.7 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.54 (dd,J=3.4, 2.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 6.74 (dd, J=3.4, 1.6 Hz,1H), 4.49 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H). MS 293 (MH⁺).

Tert-butyl methyl(2-oxo-2-(1-tosyl-1H-pyrrol-3-yl)ethyl)carbamate.Example 3.24c

Prepared in a similar manner as described in Example 3.16c starting fromtert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(methyl)carbamate(Example 3.2d) (1.62 g, 7.0 mmol) and 3-bromo-1-tosyl-1H-pyrrole(Example 3.24d) (4.5 g; 15 mmol) to obtain the desired compound as ayellow-orange oil (1.1 g, 18%). ¹H-NMR spectrum in DMSO-d₆ indicates amixture of rotamers (˜1:1). ¹H NMR (DMSO-d₆) δ: 8.24 (dt, J=5.3, 1.9 Hz,1H), 7.95 (dd, J=8.4, 2.7 Hz, 2H), 7.50-7.42 (m, 3H), 6.67 (ddd, J=6.6,3.3, 1.6 Hz, 1H), 4.45 (s, 1H), 4.44 (s, 1H), 2.79 (s, 1.3H), 2.77 (s,1.7H), 2.37 (s, 3H), 1.37 (s, 4H), 1.20 (s, 5H). MS 293 (MH⁺).

3-bromo-1-tosyl-1H-pyrrole. Example 3.24d

To a stirring solution of 1-tosyl-1-H-pyrrole (Example 3.24e) (29 g; 131mmol) in 500 mL of glacial AcOH was added a solution of Br₂ (7.0 mL; 138mmol) in 60 mL of glacial AcOH drop wise over 30 minutes. Reactionmixture was heated at 130° C. for 4 h and then concentrated undervacuum. The residue was purified on silica gel using a hexane/DCMgradient, to obtain 3-bromo-1-tosyl-1H-pyrrole as a yellow solid (13.2g, 34%). ¹H NMR (DMSO-d₆) δ: 7.90 (d, J=8.4 Hz, 2H), 7.59 (dd, J=2.4,1.6 Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.38 (dd, J=3.4, 2.4 Hz, 1H), 6.45(dd, J=3.3, 1.6 Hz, 1H), 2.37 (s, 3H). MS 301 (MH⁺).

1-tosyl-1H-pyrrole. Example 3.24e

To a suspension of NaOH (18 g; 0.60 mol) in 100 mL of DCE was addedfreshly distilled 1-H-pyrrole (10 mL; 0.15 mol). The reaction mixturewas stirred at room temperature for 30 min, then a solution ofp-toluene-sulfonyl chloride (1.22 eq; 35 g; 0.18 mol) in 40 mL of DCEwas added drop wise via addition funnel at 0° C. The reaction mixturewas then warmed to room temperature and stirred for 18 h. The reactionwas diluted with H₂O (100 mL) and extracted with DCM (3×50 mL). Thecombined organic phases were dried over MgSO₄ and solvent wasevaporated, to obtain the product as a white powder (29.0 g, 88%), whichwas 90% pure by ¹H-NMR analysis and used in the next step withoutfurther purification. ¹H NMR (DMSO-d₆) δ: 7.84 (d, J=8.4 Hz, 2H), 7.43(d, J=8.7 Hz, 2H), 7.32 (t, J=2.0 Hz, 2H), 6.34 (t, J=2.0 Hz, 2H), 2.37(s, 3H). MS: the compound did not ionize.

All of the Examples listed in Table Y, including Examples 3.25 to 3.61,were prepared through procedures outlined in Scheme 3.1 or procedureswhich are similar to the ones described in the Examples above, such asExamples 3.1 to 3.24.

The patents and publications listed herein describe the general skill inthe art and are hereby incorporated by reference in their entireties forall purposes and to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofany conflict between a cited reference and this specification, thespecification shall control. In describing embodiments of the presentapplication, specific terminology is employed for the sake of clarity.However, the invention is not intended to be limited to the specificterminology so selected. Nothing in this specification should beconsidered as limiting the scope of the present invention. All examplespresented are representative and non-limiting. The above-describedembodiments may be modified or varied, without departing from theinvention, as appreciated by those skilled in the art in light of theabove teachings.

What is claimed is:
 1. A compound having structural Formula (Ia):

or a salt or solvate thereof; wherein R¹ is optionally substitutedphenyl; R² and R³ are independently selected from the group consistingof optionally substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl; and R⁴ is optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl.
 2. The compound of claim 1, a: wherein R⁴ isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted carbocyclyl, optionallysubstituted heteroaryl, or substituted heterocyclyl.
 3. The compound ofclaim 2, wherein R¹ is phenyl.
 4. The compound of claim 2, wherein R² isoptionally substituted aryl, optionally substituted carbocyclyl,optionally substituted heteroaryl, or optionally substitutedheterocyclyl.
 5. The compound of claim 2, wherein R³ is optionallysubstituted alkyl or optionally substituted alkenyl.
 6. The compound ofclaim 5, wherein R³ is optionally substituted C₁-C₄ alkyl.
 7. Thecompound of claim 2; R² is optionally substituted carbocyclyl; and R³ isoptionally substituted alkyl.
 8. The compound of claim 2, wherein R⁴ isoptionally substituted alkyl.
 9. The compound of claim 8, wherein R⁴ isoptionally substituted C₁-C₄ alkyl.
 10. The compound of claim 1, whichis selected from the group consisting of

and a salt or solvate thereof.
 11. A composition comprising a compoundof claim 1, or a salt or solvate thereof; and at least one carrier. 12.The composition of claim 11, which is an ingestible composition orpersonal care composition.
 13. The composition of claim 12, wherein theingestible composition is a food or beverage.
 14. The composition ofclaim 11, wherein the compound in the composition is in a concentrationranging from about 1 ppm to 500 ppm.
 15. The composition of claim 11,which is a textile product or a packaging material.
 16. A compoundhaving structural Formula (Ia):

or a salt or solvate thereof; wherein R¹ is selected from the groupconsisting of pyrrolyl, thienyl, and pyridyl, each of which isoptionally substituted; R² and R³ are independently selected from thegroup consisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; and R⁴ is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryl, optionallysubstituted carbocyclyl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl.
 17. The compound of claim 16,wherein R² is optionally substituted aryl, optionally substitutedcarbocyclyl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl.
 18. The compound of claim 16, wherein R³ isoptionally substituted alkyl or optionally substituted alkenyl.
 19. Thecompound of claim 18, wherein R³ is optionally substituted C₁-C₄ alkyl.20. The compound of claim 16; R² is optionally substituted carbocyclyl;and R³ is optionally substituted alkyl.
 21. The compound of claim 16,wherein R⁴ is optionally substituted alkyl.
 22. The compound of claim21, wherein R⁴ is optionally substituted C₁-C₄ alkyl.
 23. The compoundof claim 16, which is selected from the group consisting of

and a salt or solvate thereof.